MODBASE, a database of annotated comparative protein structure models and associated resources.

MODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by MODPIPE, an automated modeling pipeline that relies primarily on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE currently contains 5,152,695 reliable models for domains in 1,593,209 unique protein sequences; only models based on statistically significant alignments and/or models assessed to have the correct fold are included. MODBASE also allows users to calculate comparative models on demand, through an interface to the MODWEB modeling server (http://salilab.org/modweb). Other resources integrated with MODBASE include databases of multiple protein structure alignments (DBAli), structurally defined ligand binding sites (LIGBASE), predicted ligand binding sites (AnnoLyze), structurally defined binary domain interfaces (PIBASE) and annotated single nucleotide polymorphisms and somatic mutations found in human proteins (LS-SNP, LS-Mut). MODBASE models are also available through the Protein Model Portal (http://www.proteinmodelportal.org/)

MODBASE: a database of annotated comparative protein structure models and associated resources

MODBASE () is a database of annotated comparative protein structure models for all available protein sequences that can be matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on MODELLER for fold assignment, sequence–structure alignment, model building and model assessment (). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, and improvements in the software for calculating the models. MODBASE currently contains 3 094 524 reliable models for domains in 1 094 750 out of 1 817 889 unique protein sequences in the UniProt database (July 5, 2005); only models based on statistically significant alignments and models assessed to have the correct fold despite insignificant alignments are included. MODBASE also allows users to generate comparative models for proteins of interest with the automated modeling server MODWEB (). Our other resources integrated with MODBASE include comprehensive databases of multiple protein structure alignments (DBAli, ), structurally defined ligand binding sites and structurally defined binary domain interfaces (PIBASE, ) as well as predictions of ligand binding sites, interactions between yeast proteins, and functional consequences of human nsSNPs (LS-SNP, )

ModBase, a database of annotated comparative protein structure models, and associated resources

ModBase (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by ModPipe, an automated modeling pipeline that relies primarily on Modeller for fold assignment, sequence–structure alignment, model building and model assessment (http://salilab.org/modeller/). ModBase currently contains 10 355 444 reliable models for domains in 2 421 920 unique protein sequences. ModBase allows users to update comparative models on demand, and request modeling of additional sequences through an interface to the ModWeb modeling server (http://salilab.org/modweb). ModBase models are available through the ModBase interface as well as the Protein Model Portal (http://www.proteinmodelportal.org/). Recently developed associated resources include the SALIGN server for multiple sequence and structure alignment (http://salilab.org/salign), the ModEval server for predicting the accuracy of protein structure models (http://salilab.org/modeval), the PCSS server for predicting which peptides bind to a given protein (http://salilab.org/pcss) and the FoXS server for calculating and fitting Small Angle X-ray Scattering profiles (http://salilab.org/foxs)

The Protein Model Portal

Structural Genomics has been successful in determining the structures of many unique proteins in a high throughput manner. Still, the number of known protein sequences is much larger than the number of experimentally solved protein structures. Homology (or comparative) modeling methods make use of experimental protein structures to build models for evolutionary related proteins. Thereby, experimental structure determination efforts and homology modeling complement each other in the exploration of the protein structure space. One of the challenges in using model information effectively has been to access all models available for a specific protein in heterogeneous formats at different sites using various incompatible accession code systems. Often, structure models for hundreds of proteins can be derived from a given experimentally determined structure, using a variety of established methods. This has been done by all of the PSI centers, and by various independent modeling groups. The goal of the Protein Model Portal (PMP) is to provide a single portal which gives access to the various models that can be leveraged from PSI targets and other experimental protein structures. A single interface allows all existing pre-computed models across these various sites to be queried simultaneously, and provides links to interactive services for template selection, target-template alignment, model building, and quality assessment. The current release of the portal consists of 7.6 million model structures provided by different partner resources (CSMP, JCSG, MCSG, NESG, NYSGXRC, JCMM, ModBase, SWISS-MODEL Repository). The PMP is available at http://www.proteinmodelportal.org and from the PSI Structural Genomics Knowledgebase

Homology modeling of &#947-aminobutyrateaminotransferase, a pyridoxal phosphate-dependent enzyme of Homo sapiens: Molecular modeling approach to rational drug design against epilepsy

γ-Aminobutyrate aminotransferase (GABA-AT) is a pyridoxal phosphate dependent homodimeric enzyme of 50-kD subunits. It is a potential drug target against epilepsy. The three-dimensional structure of GABA-AT is not experimentally known, and we thus resorted to homology modelling to build a model based on x-ray crystal structure of pig liver GABA-AT to 3.0 Å resolution. Knowledge of the threedimensional structure of GABA-AT would greatly advance the development of novel lead compounds targeting this molecule. The protein’s conservity was verified by performing multiple alignments using ClustalW and MUSCLE programs. The model was further checked for its correctness by predicting the 2D and 3D structures, which validates the structure.Key words: γ-Aminobutyrate aminotransferase (GABA-AT), epilepsy, crystal structure, homology modeling, BLAST, template

Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space

Chemokine signaling is a well-known agent of autoimmune disease, HIV infection, and cancer. Drug discovery efforts for these signaling molecules have focused on developing inhibitors targeting their associated G protein-coupled receptors. Recently, we used a structure-based approach directed at the sulfotyrosine-binding pocket of the chemokine CXCL12, and thereby demonstrated that small molecule inhibitors acting upon the chemokine ligand form an alternative therapeutic avenue. Although the 50 members of the chemokine family share varying degrees of sequence homology (some as little as 20%), all members retain the canonical chemokine fold. Here we show that an equivalent sulfotyrosine-binding pocket appears to be conserved across the chemokine superfamily. We monitored sulfotyrosine binding to four representative chemokines by NMR. The results suggest that most chemokines harbor a sulfotyrosine recognition site analogous to the cleft on CXCL12 that binds sulfotyrosine 21 of the receptor CXCR4. Rational drug discovery efforts targeting these sites may be useful in the development of specific as well as broad-spectrum chemokine inhibitors

PDBpaint, a visualization webservice to tag protein structures with sequence annotations

SUMMARY: Protein features are often displayed along the linear sequence of amino acids that make up that protein, but in reality these features occupy a position in the folded protein's three-dimensional space. Mapping sequence features to known or predicted protein structures is useful when trying to deduce the function of those features and when evaluating sequence or structural predictions. To facilitate this goal we developed PDBpaint, a simple tool that displays protein sequence features gathered from bioinformatics resources on top of protein structures, which are displayed in an interactive window (using the Jmol Java viewer). PDBpaint can be used either with existing protein structures or with novel structures provided by the user. The current version of PDBpaint allows the visualization of annotations from Pfam, ARD (detection of HEATrepeats), UniProt, TMHMM2.0 and SignalP. Users can also add other annotations manually. Availability and Implementation: PDBpaint is accessible at http://cbdm.mdc-berlin.de/~pdbpaint. Code is available from http://sourceforge.net/projects/pdbpaint. The website was implemented in Perl, with all major browsers supported. CONTACT: [email protected]

Structural genomics is the largest contributor of novel structural leverage

The Protein Structural Initiative (PSI) at the US National Institutes of Health (NIH) is funding four large-scale centers for structural genomics (SG). These centers systematically target many large families without structural coverage, as well as very large families with inadequate structural coverage. Here, we report a few simple metrics that demonstrate how successfully these efforts optimize structural coverage: while the PSI-2 (2005-now) contributed more than 8% of all structures deposited into the PDB, it contributed over 20% of all novel structures (i.e. structures for protein sequences with no structural representative in the PDB on the date of deposition). The structural coverage of the protein universe represented by today’s UniProt (v12.8) has increased linearly from 1992 to 2008; structural genomics has contributed significantly to the maintenance of this growth rate. Success in increasing novel leverage (defined in Liu et al. in Nat Biotechnol 25:849–851, 2007) has resulted from systematic targeting of large families. PSI’s per structure contribution to novel leverage was over 4-fold higher than that for non-PSI structural biology efforts during the past 8 years. If the success of the PSI continues, it may just take another ~15 years to cover most sequences in the current UniProt database

The UCSC Archaeal Genome Browser

As more archaeal genomes are sequenced, effective research and analysis tools are needed to integrate the diverse information available for any given locus. The feature-rich UCSC Genome Browser, created originally to annotate the human genome, can be applied to any sequenced organism. We have created a UCSC Archaeal Genome Browser, available at , currently with 26 archaeal genomes. It displays G/C content, gene and operon annotation from multiple sources, sequence motifs (promoters and Shine-Dalgarno), microarray data, multi-genome alignments and protein conservation across phylogenetic and habitat categories. We encourage submission of new experimental and bioinformatic analysis from contributors. The purpose of this tool is to aid biological discovery and facilitate greater collaboration within the archaeal research community