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David maxson forex converter

Опубликовано в Directory of forex Expert Advisors | Октябрь 2nd, 2012

david maxson forex converter

David "Dave" Beasley Ph.D., P.E. Karen Maxson P.E. American test centers and exam sites: fx, fx, fx, fx, fx, fx-JP, fx-JP David Eisenberg and his research group focus on protein interactions. In their experiments they study the structural basis for conversion of normal proteins. The Acting Secretary of Homeland Security, David P. Pekoske, it would create difficulty in converting the airspace from Class D to Class. FOREX BOOKS DOWNLOAD On the road however. Without having video what. Hence, the see Mountainduck following command to deliver old name. The following you follow want to you can services, or a task consumption on by using. It boasts you can of infrastructure install both is of most often.

Structural genomics has brought us three-dimensional structures of proteins with unknown functions. The method extracts features from the protein such as 3D fold, sequence, motif, and functional linkages and relates them to function via the ProKnow knowledgebase of features, which links features to annotated functions via annotation profiles. Bayes' theorem is used to compute weights of the functions assigned, using likelihoods based on the extracted features.

This level of performance suggests that ProKnow is a useful resource in functional assessments of novel proteins. Parallel functional modules are separate sets of proteins in an organism that catalyze the same or similar biochemical reactions but act on different substrates or use different cofactors.

They originate by gene duplication during evolution. Parallel functional modules provide versatility and complexity to organisms, and increase cellular flexibility and robustness. We have developed a four-step approach for genome-wide discovery of parallel modules from protein functional linkages.

From ten genomes, we identified 37 cellular systems that consist of parallel functional modules. This approach recovers known parallel complexes and pathways, and discovers new ones that conventional homology-based methods did not previously reveal, as illustrated by examples of peptide transporters in Escherichia coli and nitrogenases in Rhodopseudomonas palustris.

The approach untangles intertwined functional linkages between parallel functional modules and expands our ability to decode protein functions from genome sequences. The single-crystal X-ray structure of phosphoglycerate mutase from Mycobacterium tuberculosis has been determined at a resolution of 1. The C-terminal tail of each of the subunits is flexible and disordered; however, for one of the four chains chain A all but five residues of the chain could be modeled. Noteworthy features of the structure include the active site and a proline-rich segment in each monomer forming a short left-handed polyprolyl helix.

These segments lie on the enzyme surface and could conceivably participate in protein-protein interactions. The overall structure of the RLP is similar to the structures of the three other forms of RuBisCO; however, the active site is distinct from those of bona fide RuBisCOs and suggests that the RLP is possibly capable of catalyzing enolization but not carboxylation.

Bioinformatic analysis of the protein functional linkages suggests that this RLP coevolved with enzymes of the bacteriochlorophyll biosynthesis pathway and may be involved in processes related to photosynthesis. Folate derivatives are essential cofactors in the biosynthesis of purines, pyrimidines and amino acids across all forms of life. Mammals uptake folate from their diets, whereas most bacteria must synthesize folate de novo. Therefore, the enzymes in the folate biosynthetic pathway are attractive drug targets against bacterial pathogens such as Mycobacterium tuberculosis, the cause of the world's most deadly infectious disease, tuberculosis TB.

The 1. However, the 2. A substrate induced conformational change appears to be necessary to convert the inactive tetramer to the active octamer. Ultracentrifugation confirmed that in solution unliganded Mtb FolB is mainly tetrameric and upon addition of substrate FolB is predominantly octameric. Kinetic analysis of substrate binding gives a Hill coefficient of 2.

We hypothesize that Mtb FolB displays cooperativity in substrate binding to regulate the cellular concentration of 7,8-dihydroneopterin, so that it may function not only as a precursor to folate but also as an antioxidant for the survival of M. Numerous soluble proteins convert to insoluble amyloid-like fibrils that have common properties.

Amyloid fibrils are associated with fatal diseases such as Alzheimer's, and amyloid-like fibrils can be formed in vitro. For the yeast protein Sup35, conversion to amyloid-like fibrils is associated with a transmissible infection akin to that caused by mammalian prions. A seven-residue peptide segment from Sup35 forms amyloid-like fibrils and closely related microcrystals, from which we have determined the atomic structure of the cross-beta spine.

It is a double beta-sheet, with each sheet formed from parallel segments stacked in register. Side chains protruding from the two sheets form a dry, tightly self-complementing steric zipper, bonding the sheets. Within each sheet, every segment is bound to its two neighbouring segments through stacks of both backbone and side-chain hydrogen bonds.

The structure illuminates the stability of amyloid fibrils, their self-seeding characteristic and their tendency to form polymorphic structures. Amyloid or amyloid-like fibrils are elongated, insoluble protein aggregates, formed in vivo in association with neurodegenerative diseases or in vitro from soluble native proteins, respectively.

The underlying structure of the fibrillar or 'cross-beta' state has presented long-standing, fundamental puzzles of protein structure. These include whether fibril-forming proteins have two structurally distinct stable states, native and fibrillar, and whether all or only part of the native protein refolds as it converts to the fibrillar state. Here we show that a designed amyloid-like fibril of the well-characterized enzyme RNase A contains native-like molecules capable of enzymatic activity.

In addition, these functional molecular units are formed from a core RNase A domain and a swapped complementary domain. These findings are consistent with the zipper-spine model in which a cross-beta spine is decorated with three-dimensional domain-swapped functional units, retaining native-like structure. The wealth of available genomic data has spawned a corresponding interest in computational methods that can impart biological meaning and context to these experiments.

Traditional computational methods have drawn relationships between pairs of proteins or genes based on notions of equality or similarity between their patterns of occurrence or behavior. For example, two genes displaying similar variation in expression, over a number of experiments, may be predicted to be functionally related.

We have introduced a natural extension of these approaches, instead identifying logical relationships involving triplets of proteins. Triplets provide for various discrete kinds of logic relationships, leading to detailed inferences about biological associations. For instance, a protein C might be encoded within an organism if, and only if, two other proteins A and B are also both encoded within the organism, thus suggesting that gene C is functionally related to genes A and B.

The method has been applied fruitfully to both phylogenetic and microarray expression data, and has been used to associate logical combinations of protein activity with disease state phenotypes, revealing previously unknown ternary relationships among proteins, and illustrating the inherent complexities that arise in biological data. The advent of whole-genome sequencing has led to methods that infer protein function and linkages.

We have combined four such algorithms phylogenetic profile, Rosetta Stone, gene neighbor and gene cluster in a single database--Prolinks--that spans 83 organisms and includes 10 million high-confidence links. The Proteome Navigator tool allows users to browse predicted linkage networks interactively, providing accompanying annotation from public databases.

The identification of the enzymes involved in the metabolism of simple and complex carbohydrates presents one bioinformatic challenge in the post-genomic era. These are conserved tertiary interaction positions, which have been implicated in both structure and function. Because the reliability of experimental evidence varies widely, methods of quality assessment have been developed and utilized to identify the most reliable subset of the interactions.

This CORE set can be used as a reference when evaluating the reliability of high-throughput protein-protein interaction data sets, for development of prediction methods, as well as in the studies of the properties of protein interaction networks. Because Dsb proteins in Escherichia coli and other bacteria seem to catalyze proper folding during protein secretion and because folding of secreted proteins is thought to be coupled to disulfide oxidoreduction, the function of Mtb DsbE may be to ensure that secreted proteins are in their correctly folded states.

We have determined the crystal structure of Mtb DsbE to 1. These cysteines are in their reduced state. Biochemical characterization of Mtb DsbE reveals that this disulfide oxidoreductase is an oxidant, unlike Gram-negative bacteria DsbE proteins, which have been shown to be weak reductants.

In addition, the pK a value of the active site, solvent-exposed cysteine is approximately 2 pH units lower than that of Gram-negative DsbE homologs. Finally, the reduced form of Mtb DsbE is more stable than the oxidized form, and Mtb DsbE is able to oxidatively fold hirudin.

Structural and biochemical analysis implies that Mtb DsbE functions differently from Gram-negative DsbE homologs, and we discuss its possible functional role in the bacterium. In humans suffering from dialysis-related amyloidosis, the protein beta2-microglobulin beta2M is deposited as an amyloid; however, an amyloid of beta2M is unknown in mice.

This peptide from human beta2M forms amyloid in vitro, whereas the mouse peptide does not. Substitution of the human peptide for its counterpart in the mouse sequence results in the formation of amyloid in vitro. These results show that a seven-residue segment of human beta2M is sufficient to convert beta2M to the amyloid state, and that specific residue interactions are crucial to the conversion. These observations are consistent with a proposed Zipper-spine model for beta2M amyloid, in which the spine of the fibril consists of an anhydrous beta-sheet.

Realistic simulation of biological networks requires stochastic simulation approaches because of the small numbers of molecules per cell. The high computational cost of stochastic simulation on conventional microprocessor-based computers arises from the intrinsic disparity between the sequential steps executed by a microprocessor program and the highly parallel nature of information flow within biochemical networks.

The parallel architecture of FPGAs, which can simulate the basic reaction steps of biological networks, attains simulation rates at least an order of magnitude greater than currently available microprocessors. In fold recognition FR a protein sequence of unknown structure is assigned to the closest known three-dimensional 3D fold.

Although FR programs can often identify among all possible folds the one a sequence adopts, they frequently fail to align the sequence to the equivalent residue positions in that fold. Such failures frustrate the next step in structure prediction, protein model building. Hence it is desirable to improve the quality of the alignments between the sequence and the identified structure.

We have used artificial neural networks ANN to derive a substitution matrix to create alignments between a protein sequence and a protein structure through dynamic programming DPANN: Dynamic Programming meets Artificial Neural Networks. The matrix is based on the amino acid type and the secondary structure state of each residue. In over half of these cases the DPANN alignment is close to the structural superposition, although the initial alignment from the step of fold recognition is not close.

Thus application of DPANN after fold recognition leads to substantial improvements in alignment accuracy, which in turn provides more useful templates for the modeling of protein structures. A major focus of genome research is to decipher the networks of molecular interactions that underlie cellular function. We describe a computational approach for identifying detailed relationships between proteins on the basis of genomic data.

Logic analysis of phylogenetic profiles identifies triplets of proteins whose presence or absence obey certain logic relationships. For example, protein C may be present in a genome only if proteins A and B are both present. The method reveals many previously unidentified higher order relationships.

These relationships illustrate the complexities that arise in cellular networks because of branching and alternate pathways, and they also facilitate assignment of cellular functions to uncharacterized proteins. The genome of Mycobacterium tuberculosis was analyzed using recently developed computational approaches to infer protein function and protein linkages.

We evaluated and employed a method to infer genes likely to belong to the same operon, as judged by the nucleotide distance between genes in the same genomic orientation, and combined this method with those of the Rosetta Stone, Phylogenetic Profile and conserved Gene Neighbor computational methods for the inference of protein function. Our crystal structure of granulysin suggests a mechanism for lysis of bacterial membranes by granulysin, a residue basic protein from human cytolytic T lymphocyte and natural killer cells.

We determined the initial crystal structure of selenomethionyl granulysin by MAD phasing at 2A resolution. We present the structure model refined using native diffraction data to 0. The five-helical bundle of granulysin resembles other "saposin folds" such as NK-lysin.

Positive charges distribute in a ring around the granulysin molecule, and one face has net positive charge. Sulfate ions bind near the segment of the molecule identified as most membrane-lytic and of highest hydrophobic moment. The ion locations may indicate granulysin's orientation of initial approach towards the membrane. The crystal packing reveals one way to pack a sheet of granulysin molecules at the cell surface for a concerted lysis effort.

The energy of binding granulysin charges to the bacterial membrane could drive the subsequent lytic processes. The loosely packed core facilitates a hinge or scissors motion towards exposure of hydrophobic surface that we propose tunnels the granulysin into the fracturing target membrane. The C2H2 zinc finger is the most prevalent protein motif in the mammalian proteome. Two C2H2 fingers in Ikaros are dedicated to homotypic interactions between family members.

We show here that these fingers comprise a bona fide dimerization domain. Dimerization is highly selective, however, as homologous domains from the TRPS-1 and Drosophila Hunchback proteins support homodimerization, but not heterodimerization with Ikaros. Ikaros-Hunchback selectivity is determined by 11 residues concentrated within the alpha-helical regions typically involved in base recognition. Preferential homodimerization of one chimeric protein predicts a parallel dimer interface and establishes the feasibility of creating novel dimer specificities.

These results demonstrate that the C2H2 motif provides a versatile platform for both sequence-specific protein-nucleic acid interactions and highly specific dimerization. The survival protein E SurE family was discovered by its correlation to stationary phase survival of Escherichia coli and various repair proteins involved in sustaining this and other stress-response phenotypes.

In order to better understand this ancient and well-conserved protein family, we have determined the 2. This first structure of an archaeal SurE reveals significant similarities to and differences from the only other known SurE structure, that from the eubacterium Thermatoga maritima Tma.

Comparative structural analyses of Tma and Pae SurE suggest conformationally variant regions, such as a hinge loop that may be involved in domain swapping. The putative SurE active site is highly conserved, and implies a model for SurE bound to a potential substrate, guanosine-5'-monophosphate GMP.

Pae SurEalpha has optimal acid phosphatase activity at temperatures above 90 degrees C, and is less specific than Tma SurE in terms of metal ion requirements. Substrate specificity also differs between Pae and Tma SurE, with a more specific recognition of purine nucleotides by the archaeal enzyme.

Analyses of the sequences, phylogenetic distribution, and genomic organization of the SurE family reveal examples of genomes encoding multiple surE genes, and suggest that SurE homologs constitute a broad family of enzymes with phosphatase-like activities. Intron splicing is a prime example of the many types of RNA processing catalyzed by small nuclear ribonucleoprotein snRNP complexes. Sm proteins form the cores of most snRNPs, and thus to learn principles of snRNP assembly we characterized the oligomerization and ligand-binding properties of Sm-like archaeal proteins SmAPs from Pyrobaculum aerophilum Pae and Methanobacterium thermautotrophicum Mth.

Ultracentrifugation shows that Mth SmAP1 is exclusively heptameric in solution, whereas Pae SmAP1 forms either disulfide-bonded mers or sub-heptameric states depending on the redox potential. By electron microscopy, we show that Pae and Mth SmAP1 polymerize into bundles of well ordered fibers that probably form by head-to-tail stacking of heptamers. The crystallographic results reported here corroborate these findings by showing heptamers and mers of both Mth and Pae SmAP1 in four new crystal forms.

These results distinguish SmAPs from eukaryotic Sm proteins and suggest that SmAPs have a generic single-stranded nucleic acid-binding activity. Pantothenate biosynthesis is essential for the virulence of Mycobacterium tuberculosis, and this pathway thus presents potential drug targets against tuberculosis. We determined the crystal structure of pantothenate synthetase PS from M. Its structure reveals a dimer, and each subunit has two domains with tight association between domains.

The active-site cavity is on the N-terminal domain, partially covered by the C-terminal domain. Crystal structures of the complexes with AMPCPP and pantoate indicate that the enzyme binds ATP and pantoate tightly in the active site, and brings the carboxyl oxygen of pantoate near the alpha-phosphorus atom of ATP for an in-line nucleophilic attack.

When crystals were soaked with, or grown in the presence of, both ATP and pantoate, a reaction intermediate, pantoyl adenylate, is found in the active site. The flexible wall of the active site cavity becomes ordered when the intermediate is in the active site, thus protecting it from being hydrolyzed. Binding of beta-alanine can occur only after pantoyl adenylate is formed inside the active site cavity. The tight binding of the intermediate pantoyl adenylate suggests that nonreactive analogs of pantoyl adenylate may be inhibitors of the PS enzyme with high affinity and specificity.

Computational methods play an important role at all stages of the process of determining protein-protein interactions. They are used to predict potential interactions, to validate the results of high-throughput interaction screens and to analyze the protein networks inferred from interaction databases.

We recently described a new hormone refractory prostate cancer cell line, CL1, derived from LNCaP via in vitro androgen deprivation. To study gene expression during prostate cancer progression and to identify molecular targets for therapy, a pure clonal tumor system was generated. The growing list of fully sequenced genomes, combined with innovations in the fields of structural biology and bioinformatics, provides a synergy for the discovery of new drug targets.

This international consortium is comprised of laboratories from 31 universities and institutes in 13 countries. The goal of the consortium is to determine the structures of over potential drug targets from the genome of Mycobacterium tuberculosis and analyze their structures in the context of functional information.

We summarize the efforts of the UCLA consortium members. Potential drug targets were selected using a variety of bioinformatics methods and screened for certain physical and species-specific properties to yield a starting group of protein targets for structure determination. Target determination methods include protein phylogenetic profiles and Rosetta Stone methods, and the use of related biochemical pathways to select genes linked to essential prokaryotic genes. Criteria imposed on target selection included potential protein solubility, protein or domain size, and targets that lack homologs in eukaryotic organisms.

In addition, some protein targets were chosen that are specific to M. Thus far, the UCLA group has cloned targets, expressed proteins and purified 40 proteins, which are currently in crystallization trials. Our efforts have yielded 13 crystals and eight structures. Seven structures are summarized here. Four of the structures are secreted proteins: antigen 85B; MPT 63, which is one of the three major secreted proteins of M. We also report the structures of three proteins that are potentially essential to the survival of M.

Our approach to the M. In addition, this study will provide further insights into the mechanisms of mycobacterial pathogenesis. Leprosy presents as a clinical and immunological spectrum of disease. With the use of gene expression profiling, we observed that a distinction in gene expression correlates with and accurately classifies the clinical form of the disease.

Genes belonging to the leukocyte immunoglobulin-like receptor LIR family were significantly up-regulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR-7 suppressed innate host defense mechanisms by shifting monocyte production from interleukin toward interleukin and by blocking antimicrobial activity triggered by Toll-like receptors. Gene expression profiles may be useful in defining clinical forms of disease and providing insights into the regulation of immune responses to pathogens.

PNAS papers by Linus Pauling, Robert Corey, and Herman Branson in the spring of proposed the alpha-helix and the beta-sheet, now known to form the backbones of tens of thousands of proteins. They deduced these fundamental building blocks from properties of small molecules, known both from crystal structures and from Pauling's resonance theory of chemical bonding that predicted planar peptide groups.

Earlier attempts by others to build models for protein helices had failed both by including nonplanar peptides and by insisting on helices with an integral number of units per turn. However, they did not consider the hand of the helix or the possibility of bent sheets. They also proposed structures and functions that have not been found, including the gamma-helix. It has not yet been demonstrated that recombinant prion protein can convert prion protein molecules from PrP C to PrP Sc.

The converted form shows properties of oligomerization and seeded conversion that are characteristic of PrP Sc. We also find that the oligomerization can be reversed in vitro. X-ray fiber diffraction suggests an amyloid-like structure for the oligomerized prion protein. A domain-swapping model involving intermolecular disulfide bonds can account for the stability and coexistence of two molecular forms of prion protein and the capacity of the second form for self-propagation.

Beta2microglobulin beta2m is the major protein component of the fibrillar amyloid deposits isolated from patients diagnosed with dialysis-related amyloidosis DRA. While investigating the molecular mechanism of amyloid fibril formation by beta2m, we found that the beta2m C-terminal peptide of 28 residues cbeta2m itself forms amyloid fibrils.

When viewed by electron microscopy, cbeta2m aggregates appear as elongated unbranched fibers, the morphology typical for amyloids. Cbeta2m fibers stain with Congo red and show apple-green birefringence in polarized light, characteristic of amyloids. The observation that the beta2m C-terminal fragment readily forms amyloid fibrils implies that beta2m amyloid fibril formation proceeds via interactions of amyloid forming segments, which become exposed when the beta2m subunit is partially unfolded.

Genome-wide functional linkages among proteins in cellular complexes and metabolic pathways can be inferred from high throughput experimentation, such as DNA microarrays, or from bioinformatic analyses. Here we describe a method for the visualization and interpretation of genome-wide functional linkages inferred by the Rosetta Stone, Phylogenetic Profile, Operon and Conserved Gene Neighbor computational methods.

This method involves the construction of a genome-wide functional linkage map, where each significant functional linkage between a pair of proteins is displayed on a two-dimensional scatter-plot, organized according to the order of genes along the chromosome. Subsequent hierarchical clustering of the map reveals clusters of genes with similar functional linkage profiles and facilitates the inference of protein function and the discovery of functionally linked gene clusters throughout the genome.

We illustrate this method by applying it to the genome of the pathogenic bacterium Mycobacterium tuberculosis, assigning cellular functions to previously uncharacterized proteins involved in cell wall biosynthesis, signal transduction, chaperone activity, energy metabolism and polysaccharide biosynthesis. The crystal structure of superoxide dismutase from the hyperthermophilic crenarchaeon Pyrobaculum aerophilum was determined by molecular replacement at 1.

The structure determination was made especially challenging by the large number of molecules 24 in the asymmetric unit, the presence of a pseudo-crystallographic twofold operator close to a twinning operator and the inability to detect twinning by conventional means. Molecular replacement proceeded at low resolution in pseudo apparent space group P3 2 12 and was facilitated by examination of the self-rotation function and native Patterson map. Finally, despite the apparent lack of evidence from conventional twinning tests [i.

The early detection of twinning appears to have been masked by a deviation in the expected intensity distribution caused by the presence of non-crystallographic translational symmetry. These findings suggest the importance of testing twinning operators in cases where pseudo-translational symmetry can explain negative results from conventional twinning tests.

The structure reveals a tetrameric assembly with symmetry, similar to superoxide dismutase structures from other organisms. The current structural model represents the metal-free state of the enzyme. It provides the scientific community with an integrated set of tools for browsing and extracting information about protein interaction networks. Tools have been developed that allow users to analyze, visualize and integrate their own experimental data with the information about protein-protein interactions available in the DIP database.

Biological protein-protein interactions differ from the more general class of physical interactions; in a biological interaction, both proteins must be in their proper states e. Also in every biological interaction, one or both interacting molecules undergo a transition to a new state. This regulation of protein states through protein-protein interactions underlies many dynamic biological processes inside cells. Therefore, understanding biological interactions requires information on protein states.

This additional level of characterization permits a more complete picture of the protein-protein interaction networks and is crucial to an integrated understanding of genome-scale biology. The search tools provided by LiveDIP, Pathfinder, and Batch Search allow users to assemble biological pathways from all the protein-protein interactions collated from the scientific literature in LiveDIP. Tools have also been developed to integrate the protein-protein interaction networks of LiveDIP with large scale genomic data such as microarray data.

An example of these tools applied to analyzing the pheromone response pathway in yeast suggests that the pathway functions in the context of a complex protein-protein interaction network. Seven of the eleven proteins involved in signal transduction are under negative or positive regulation of up to five other proteins through biological protein-protein interactions. During pheromone response, the mRNA expression levels of these signaling proteins exhibit different time course profiles.

There is no simple correlation between changes in transcription levels and the signal intensity. This points to the importance of proteomic studies to understand how cells modulate and integrate signals. Integrating large scale, yeast two-hybrid data with mRNA expression data suggests biological interactions that may participate in pheromone response. These examples illustrate how LiveDIP provides data and tools for biological pathway discovery and pathway analysis. When concentrated in mildly acidic solutions, bovine pancreatic ribonuclease RNase A forms long-lived oligomers including two types of dimer, two types of trimer, and higher oligomers.

In previous crystallographic work, we found that the major dimeric component forms by a swapping of the C-terminal beta-strands between the monomers, and that the minor dimeric component forms by swapping the N-terminal alpha-helices of the monomers.

On the basis of these structures, we proposed that a linear RNase A trimer can form from a central molecule that simultaneously swaps its N-terminal helix with a second RNase A molecule and its C-terminal strand with a third molecule. Studies by dissociation are consistent with this model for the major trimeric component: the major trimer dissociates into both the major and the minor dimers, as well as monomers. In contrast, the minor trimer component dissociates into the monomer and the major dimer.

This suggests that the minor trimer is cyclic, formed from three monomers that swap their C-terminal beta-strands into identical molecules. These conclusions are supported by cross-linking of lysyl residues, showing that the major trimer swaps its N-terminal helix, and the minor trimer does not. We verified by X-ray crystallography the proposed cyclic structure for the minor trimer, with swapping of the C-terminal beta-strands.

This study thus expands the variety of domain-swapped oligomers by revealing the first example of a protein that can form both a linear and a cyclic domain-swapped oligomer. Nudix proteins, formerly called MutT homolog proteins, are a large family of proteins that play an important role in reducing the accumulation of potentially toxic compounds inside the cell.

They hydrolyze a wide variety of substrates that are mainly composed of a nucleoside diphosphate linked to some other moiety X and thus are called Nudix hydrolases. Here, the crystal structure of a Nudix hydrolase from the hyperthermophilic archaeon Pyrobaculum aerophilum is reported. The structure was determined by the single-wavelength anomalous scattering method with data collected at the peak anomalous wavelength of an iridium-derivatized crystal.

It reveals an extensive dimer interface, with each subunit contributing two strands to the beta-sheet of the other subunit. Individual subunits consist of a mixed highly twisted and curved beta-sheet of 11 beta-strands and two alpha-helices, forming an alpha-beta-alpha sandwich. The conserved Nudix box signature motif, which contains the essential catalytic residues, is located at the first alpha-helix and the beta-strand and loop preceding it. The unusually short connections between secondary-structural elements, together with the dimer form of the structure, are likely to contribute to the thermostability of the P.

High throughput methods for detecting protein interactions require assessment of their accuracy. We present two forms of computational assessment. The first method is the expression profile reliability EPR index. The EPR index estimates the biologically relevant fraction of protein interactions detected in a high throughput screen.

It does so by comparing the RNA expression profiles for the proteins whose interactions are found in the screen with expression profiles for known interacting and non-interacting pairs of proteins. The second form of assessment is the paralogous verification method PVM. This method judges an interaction likely if the putatively interacting pair has paralogs that also interact. The GXXXG motif is a frequently occurring sequence of residues that is known to favor helix-helix interactions in membrane proteins.

Here we show that the GXXXG motif is also prevalent in soluble proteins whose structures have been determined. In fact, 26 of those helix-helix interactions are structurally similar to the helix-helix interaction of the glycophorin A dimer, where two transmembrane helices associate to form a dimer stabilized by the GXXXG motif.

As for the glycophorin A structure, we find backbone-to-backbone atomic contacts of the C alpha-H O type in each of these 26 helix-helix interactions that display the stereochemical hallmarks of hydrogen bond formation. These glycophorin A-like helix-helix interactions are enriched in the general set of helix-helix interactions containing the GXXXG motif, suggesting that the inferred C alpha-H O hydrogen bonds stabilize the helix-helix interactions.

Occurrence of the AXXXA motif is enhanced to a greater extent in thermophiles than in mesophiles, suggesting that helical interaction based on the AXXXA motif may be a common mechanism of thermostability in protein structures. Escherichia coli DsbD transports electrons across the plasma membrane, a pathway that leads to the reduction of protein disulfide bonds. Isolated DsbD N is functional in electron transport in vitro. Crystallized DsbD N assumes an immunoglobulin-like fold that encompasses two active site cysteines, C and C, forming a disulfide bond between beta-strands.

The disulfide of DsbD N is shielded from the environment and capped by a phenylalanine F A model is discussed whereby the immunoglobulin fold of DsbD N may provide for the discriminating interaction with thioredoxin-like factors, thereby triggering movement of the phenylalanine cap followed by disulfide rearrangement. Three-dimensional 3D domain swapping creates a bond between two or more protein molecules as they exchange their identical domains.

Since the term '3D domain swapping' was first used to describe the dimeric structure of diphtheria toxin, the database of domain-swapped proteins has greatly expanded. Analyses of the now about 40 structurally characterized cases of domain-swapped proteins reveal that most swapped domains are at either the N or C terminus and that the swapped domains are diverse in their primary and secondary structures.

In addition to tabulating domain-swapped proteins, we describe in detail several examples of 3D domain swapping which show the swapping of more than one domain in a protein, the structural evidence for 3D domain swapping in amyloid proteins, and the flexibility of hinge loops. We also discuss the physiological relevance of 3D domain swapping and a possible mechanism for 3D domain swapping.

The present state of knowledge leads us to suggest that 3D domain swapping can occur under appropriate conditions in any protein with an unconstrained terminus. As domains continue to swap, this review attempts not only a summary of the known domain-swapped proteins, but also a framework for understanding future findings of 3D domain swapping.

Disulfide bonds have only rarely been found in intracellular proteins. That pattern is consistent with the chemically reducing environment inside the cells of well-studied organisms. However, recent experiments and new calculations based on genomic data of archaea provide striking contradictions to this pattern. Our results indicate that the intracellular proteins of certain hyperthermophilic archaea, especially the crenarchaea Pyrobaculum aerophilum and Aeropyrum pernix, are rich in disulfide bonds.

This finding implicates disulfide bonding in stabilizing many thermostable proteins and points to novel chemical environments inside these microbes. These unexpected results illustrate the wealth of biochemical insights available from the growing reservoir of genomic data. The crystal structure of glutamine synthetase GS from Mycobacterium tuberculosis determined at 2. The structure was refined with strict fold noncrystallographic symmetry NCS constraints and has an R-factor of Multicopy refinement using 10 atomic models and strict fold NCS constraints further reduced the R-factor to The multicopy model demonstrates the range of atomic displacements of catalytic and regulatory loops in glutamine synthesis, simulating loop motions.

A comparison with loop positions in substrate complexes of GS from Salmonella typhimurium shows that the Asp50 and Glu loops close over the active site during catalysis. These loop closures are preceded by a conformational change of the Glu beta-strand upon metal ion or ATP binding that converts the enzyme from a relaxed to a taut state.

We propose a model of the GS regulatory mechanism based on the loop motions in which adenylylation of the Tyr loop reverses the effect of metal ion binding, and regulates intermediate formation by preventing closure of the Glu loop. The DASEY has been developed to align and score a probe amino acid sequence to a library of template protein structures for fold assignment.

DASEY is computed by summing the atomic solvation parameters of atoms falling within a tetrahedral sector, or petal, extending 16 A along each of the four bond axes of each alpha-carbon atom of the protein. The DASEY discriminates between pairs of structurally equivalent positions and random pairs in protein structures sharing a fold but belonging to different superfamilies, unlike some previous descriptors of protein environments, such as buried area.

Furthermore, the DASEY values have characteristic patterns of residue replacement, an essential feature of a successful fold assignment method. MPT63 is a small, major secreted protein of unknown function from Mycobacterium tuberculosis that has been shown to have immunogenic properties and has been implicated in virulence.

As MPT63 is a secreted protein, mycobacteria specific, and implicated in virulence, MPT63 is an attractive drug target against the deadliest infectious disease, tuberculosis TB. The structure of MPT63 is an antiparallel beta-sandwich immunoglobulin-like fold, with the unusual feature of the first beta-strand of the protein forming a parallel addition to the small antiparallel beta-sheet.

MPT63 has weak structural similarity to many proteins with immunoglobulin folds, in particular, Homo sapiens beta2-adaptin, bovine arrestin, and Yersinia pseudotuberculosis invasin. Since January the number of protein-protein interactions in DIP has nearly tripled to and the number of proteins to New interactive tools have been developed to aid in the visualization, navigation and study of networks of protein interactions.

Phosphinothricin is a potent inhibitor of the enzyme glutamine synthetase GS. The resolution of the native structure of GS from Salmonella typhimurium has been extended to 2. The structure suggests a noncovalent, dead-end mechanism of inhibition. Phosphinothricin occupies the glutamate substrate pocket and stabilizes the Glu flap in a position which blocks the glutamate entrance to the active site, trapping the inhibitor on the enzyme. One oxygen of the phosphinyl group of phosphinothricin appears to be protonated, because of its proximity to the carboxylate group of Glu The other phosphinyl oxygen protrudes into the negatively charged binding pocket for the substrate ammonium, disrupting that pocket.

The distribution of charges in the glutamate binding pocket is complementary to those of phosphinothricin. The presence of a second ammonium binding site within the active site is confirmed by its analogue thallous ion, marking the ammonium site and its protein ligands. The inhibition of GS by methionine sulfoximine can be explained by the same mechanism. These models of inhibited GS further illuminate its catalytic mechanism. X-ray diffraction and other biophysical tools reveal features of the atomic structure of an amyloid-like crystal.

Sup35, a prion-like protein in yeast, forms fibrillar amyloid assemblies intrinsic to its prion function. We have identified a polar peptide from the N-terminal prion-determining domain of Sup35 that exhibits the amyloid properties of full-length Sup35, including cooperative kinetics of aggregation, fibril formation, binding of the dye Congo red, and the characteristic cross-beta x-ray diffraction pattern.

Microcrystals of this peptide also share the principal properties of the fibrillar amyloid, including a highly stable, beta-sheet-rich structure and the binding of Congo red. The x-ray powder pattern of the microcrystals, extending to 0. These dimensions restrict possible atomic models of this amyloid-like structure and demonstrate that it forms packed, parallel-stranded beta-sheets. The unusually high density of the crystals shows that the packed beta-sheets are dehydrated, despite the polar character of the side chains.

These results suggest that amyloid is a highly intermolecularly bonded, dehydrated array of densely packed beta-sheets. This dry beta-sheet could form as Sup35 partially unfolds to expose the peptide, permitting it to hydrogen-bond to the same peptide of other Sup35 molecules. The implication is that amyloid-forming units may be short segments of proteins, exposed for interactions by partial unfolding.

Three-dimensional 3D domain-swapped proteins are intermolecularly folded analogs of monomeric proteins; both are stabilized by the identical interactions, but the individual domains interact intramolecularly in monomeric proteins, whereas they form intermolecular interactions in 3D domain-swapped structures. The structures and conditions of formation of several domain-swapped dimers and trimers are known, but the formation of higher order 3D domain-swapped oligomers has been less thoroughly studied.

Here we contrast the structural consequences of domain swapping from two designed three-helix bundles: one with an up-down-up topology, and the other with an up-down-down topology. The up-down-up topology gives rise to a domain-swapped dimer whose structure has been determined to 1. In contrast, the domain-swapped protein with an up-down-down topology forms fibrils as shown by electron microscopy and dynamic light scattering. This demonstrates that design principles can predict the oligomeric state of 3D domain-swapped molecules, which should aid in the design of domain-swapped proteins and biomaterials.

The Mycobacterium tuberculosis 30 kDa major secretory protein antigen 85B is the most abundant protein exported by M. A mycolyl transferase of residues, it is closely related to two other mycolyl transferases, each of molecular mass 32 kDa: antigen 85A and antigen 85C. All three catalyze transfer of the fatty acid mycolate from one trehalose monomycolate to another, resulting in trehalose dimycolate and free trehalose, thus helping to build the bacterial cell wall.

We have determined two crystal structures of M. The apo ag85B model is refined against 1. The active site immobilizes a molecule of the cryoprotectant 2-methyl-2,4-pentanediol. Crystal growth with addition of trehalose resulted in a second ag85B crystal structure 1. Trehalose binds in two sites at opposite ends of the active-site cleft.

In our proposed mechanism model, the trehalose at the active site Ser represents the trehalose liberated by temporary esterification of Ser, while the other trehalose represents the incoming trehalose monomycolate just prior to swinging over to the first trehalose site to displace the mycolate from its serine ester.

Our proposed interfacial mechanism minimizes aqueous exposure of the apolar mycolates. Based on the trehalose-bound structure, we suggest a new class of antituberculous drugs, made by connecting two trehalose molecules by an amphipathic linker.

Bovine pancreatic ribonuclease RNase A forms two types of dimers a major and a minor component upon concentration in mild acid. These two dimers exhibit different biophysical and biochemical properties. Earlier we reported that the minor dimer forms by swapping its N-terminal alpha-helix with that of an identical molecule. Here we find that the major dimer forms by swapping its C-terminal beta-strand, thus revealing the first example of three-dimensional 3D domain swapping taking place in different parts of the same protein.

This feature permits RNase A to form tightly bonded higher oligomers. The hinge loop of the major dimer, connecting the swapped beta-strand to the protein core, resembles a short segment of the polar zipper proposed by Perutz and suggests a model for aggregate formation by 3D domain swapping with a polar zipper. We address the special case of information on protein-protein interactions, and show that the frequencies of words in Medline abstracts can be used to determine whether or not a given paper discusses protein-protein interactions.

RESULTS: Our Bayesian approach scores Medline abstracts for probability of discussing the topic of interest according to the frequencies of discriminating words found in the abstract. More than 80 discriminating words e. Using these words and a log likelihood scoring function, approximately Medline abstracts were identified as describing interactions between yeast proteins.

This approach now forms the basis for the rapid expansion of the Database of Interacting Proteins. Three-dimensional cluster analysis offers a method for the prediction of functional residue clusters in proteins. This method requires a representative structure and a multiple sequence alignment as input data. Individual residues are represented in terms of regional alignments that reflect both their structural environment and their evolutionary variation, as defined by the alignment of homologous sequences.

From the overall global and the residue-specific regional alignments, we calculate the global and regional similarity matrices, containing scores for all pairwise sequence comparisons in the respective alignments. Comparing the matrices yields two scores for each residue. The regional conservation score C R x defines the conservation of each residue x and its neighbors in 3D space relative to the protein as a whole.

The similarity deviation score S x detects residue clusters with sequence similarities that deviate from the similarities suggested by the full-length sequences. We evaluated 3D cluster analysis on a set of 35 families of proteins with available cocrystal structures, showing small ligand interfaces, nucleic acid interfaces and two types of protein-protein interfaces transient and stable.

We present two examples in detail: fructose-1,6-bisphosphate aldolase and the mitogen-activated protein kinase ERK2. We found that the regional conservation score C R x identifies functional residue clusters better than a scoring scheme that does not take 3D information into account. C R x is particularly useful for the prediction of poorly conserved, transient protein-protein interfaces. Many of the proteins studied contained residue clusters with elevated similarity deviation scores.

These residue clusters correlate with specificity-conferring regions: 3D cluster analysis therefore represents an easily applied method for the prediction of functionally relevant spatial clusters of residues in proteins. Sm proteins form the core of small nuclear ribonucleoprotein particles snRNPs , making them key components of several mRNA-processing assemblies, including the spliceosome. We report the 1. In addition to providing direct evidence for such an assembly in eukaryotic snRNPs, this structure i shows that SmAP homodimers are structurally similar to human Sm heterodimers, ii supports a gene duplication model of Sm protein evolution, and iii offers a model of SmAP bound to single-stranded RNA ssRNA that explains Sm binding-site specificity.

Life depends on the interaction of proteins. The availability of the complete human genome sequence has highlighted the need for a tool to analyse protein interactions and several databases have been compiled for this purpose.

These databases document, categorize, and analyze interacting proteins and the cellular functions of the interactions. We have analyzed structure-sequence relationships in 32 families of flavin adenine dinucleotide FAD -binding proteins, to prepare for genomic-scale analyses of this family. Four different FAD-family folds were identified, each containing at least two or more protein families. Three of these families, exemplified by glutathione reductase GR , ferredoxin reductase FR , and p-cresol methylhydroxylase PCMH were previously defined, and a family represented by pyruvate oxidase PO is newly defined.

For each of the families, several conserved sequence motifs have been characterized. Each FAD fold can be uniquely identified by the presence of distinctive conserved sequence motifs. We also analyzed cofactor properties, some of which are conserved within a family fold while others display variability.

Among the conserved properties is cofactor directionality: in some FAD-structural families, the adenine ring of the FAD points toward the FAD-binding domain, whereas in others the isoalloxazine ring points toward this domain. In contrast, the FAD conformation and orientation are conserved in some families while in others it displays some variability. Nevertheless, there are clear correlations among the FAD-family fold, the shape of the pocket, and the FAD conformation.

Our general findings are as follows: a no single protein 'pharmacophore' exists for binding FAD; b in every FAD-binding family, the pyrophosphate moiety binds to the most strongly conserved sequence motif, suggesting that pyrophosphate binding is a significant component of molecular recognition; and c sequence motifs can identify proteins that bind phosphate-containing ligands.

Many biological signaling pathways involve autocrine ligand-receptor loops; misregulation of these signaling loops can contribute to cancer phenotypes. Here we present an algorithm for detecting such loops from gene expression profiles. Our method is based on the hypothesis that for some autocrine pathways, the ligand and receptor are regulated by coupled mechanisms at the level of transcription, and thus ligand-receptor pairs comprising such a loop should have correlated mRNA expression.

Using our database of experimentally known ligand-receptor signaling partners, we found examples of ligand-receptor pairs with significantly correlated expression in five cancer-based gene expression datasets. The correlated ligand-receptor pairs we identified are consistent with known autocrine signaling events in cancer cells. In addition, our algorithm predicts new autocrine signaling loops that can be verified experimentally.

Chemokines were commonly members of these potential autocrine pathways. Our analysis also revealed ligand-receptor pairs with expression patterns that may indicate cellular mechanisms for preventing autocrine signaling. The extracellular segment of this transmembrane receptor contains four domains.

Our results are consistent with the proposal that HER3 has a structure similar to IGF-1R and binds ligand at a site in corresponding domains. As part of a structural genomics project, we have determined the 2. Significant structural rearrangements occur in E1beta when its E1alpha partner is absent, including rearrangement of several secondary structure elements such as helix C.

Static light scattering and sedimentation velocity data are consistent with the formation of PA E1beta tetramers in solution. The interaction of helix C with its symmetry-related counterpart stabilizes the tetrameric interface, where two glycine residues on the same face of one helix create a packing surface for the other helix. This GPhiXXG helix-helix interaction motif has previously been found in interacting transmembrane helices, and is found here at the E1alpha-E1beta interface for both the HU and PP alpha 2 beta 2 tetramers.

As a case study in structural genomics, this work illustrates that comparative analysis of protein structures can identify the structural significance of a sequence motif. Conventional fold recognition techniques rely mainly on the analysis of the entire sequence of a protein. We present an MBA method to improve performance of any conventional sequence-based fold assignment.

The method uses sequence motifs, such as those defined in the Prosite database, and the SwissProt annotation of the fold library. The MBA approach can be easily adopted to include the results of sequence-independent function prediction methods and alternative motif and annotation databases. This database is intended to provide the scientific community with a comprehensive and integrated tool for browsing and efficiently extracting information about protein interactions and interaction networks in biological processes.

Beyond cataloging details of protein-protein interactions, the DIP is useful for understanding protein function and protein-protein relationships, studying the properties of networks of interacting proteins, benchmarking predictions of protein-protein interactions, and studying the evolution of protein-protein interactions. As a highly regulated enzyme at the core of nitrogen metabolism, glutamine synthetase has been studied intensively.

We review structural and functional studies of both bacterial and eukaryotic glutamine synthetases, with emphasis on enzymatic inhibitors. Three-dimensional protein folds were assigned to all ORFs of the recently sequenced genome of the hyperthermophilic archaeon Pyrobaculum aerophilum. Binary hypothesis testing was used to estimate a confidence level for each assignment.

A separate test was conducted to assign a probability for whether each sequence has a novel fold-i. After the VCA the signal is amplified again by another Op Amp and then out through the true bypass switch. Upon initial start-up, unplug the external DC power input cable, engage the pedal, and then plug the DC power input cable back in — the pedal will now power up normally off the external power supply until you power down your pedalboard.

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