Structure-based Active Site Profiles for Genome Analysis and Functional Family Subclassification

Cammer, Stephen; Hoffman, Brian T.; Speir, Jeffrey A.; Canady, Mary A.; Nelson, Melanie; Knutson, Stacy T.; Gallina, Marijo; Baxter, Susan M.; Fetrow, Jacquelyn S.

doi:10.1016/j.jmb.2003.09.062

Cited by 53 publications

(91 citation statements)

References 51 publications

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“…[14][15][16][17][18][19]58 Like CPASS, these approaches are using information about the protein's active site to make a correlation with a known protein and assign a function to the unknown protein. Nevertheless, the application and details of the CPASS approach are fundamentally distinct from these other methods.…”

Section: Comparison Of Cpass To Other Methodsmentioning

confidence: 99%

“…This is typically accomplished by developing structural descriptors of active sites for defi ned protein functional classes and then fi tting these structural templates to novel folds to identify putative active sites and annotate the hypothetical proteins. A variety of approaches are being applied that include aligning structures to match a few consensus or enzymatic catalytic residues, [14][15][16][17][18][19][20][21][22][23] identifi cation of cavities consistent with shapes of known ligands, 24 a sequence independent force fi eld to extract common active site features, 25 theoretical prediction of titration curves, 26 using chemical properties and electrostatic potentials of amino acid residues consistent with active site characteristics, 27,28 neural network analysis of spatial clustering of residues, 29 and conserved residues from multiple sequence alignments (phylogenetic motifs). 20,30 Nevertheless, direct experimental observation of protein-ligand interactions are a more reliable mechanism for the proper and accurate identifi cation of protein active sites.…”

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confidence: 99%

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Comparison of protein active site structures for functional annotation of proteins and drug design

et al. 2006

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Rapid and accurate functional assignment of novel proteins is increasing in importance, given the completion of numerous genome sequencing projects and the vastly expanding list of unannotated proteins. Traditionally, global primary‐sequence and structure comparisons have been used to determine putative function. These approaches, however, do not emphasize similarities in active site configurations that are fundamental to a protein's activity and highly conserved relative to the global and more variable structural features. The Comparison of Protein Active Site Structures (CPASS) database and software enable the comparison of experimentally identified ligand‐binding sites to infer biological function and aid in drug discovery. The CPASS database comprises the ligand‐defined active sites identified in the protein data bank, where the CPASS program compares these ligand‐defined active sites to determine sequence and structural similarity without maintaining sequence connectivity. CPASS will compare any set of ligand‐defined protein active sites, irrespective of the identity of the bound ligand. Proteins 2006. © 2006 Wiley‐Liss, Inc.

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Section: Comparison Of Cpass To Other Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Comparison of protein active site structures for functional annotation of proteins and drug design

et al. 2006

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“…The active site signatures of the 25 COX structures were constructed as described in [40]; the following key functional residues were identified: Tyr 385, Arg 120, and Tyr 355. Any residue that contains an atom located within 10 ä of the center of mass of these key residues was identified.…”

Section: Experimental Partmentioning

confidence: 99%

“…Signatures were aligned using CLUSTALW [43] to create the complete active site profile (ASP). An ASP score is based only on sequence information and is calculated using positive weights for sequence identity and similarity, and negative weights for gaps [40].…”

Section: Experimental Partmentioning

confidence: 99%

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Chemical and Structural Diversity in Cyclooxygenase Protein Active Sites

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Bayram

Tan

et al. 2005

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A major pharmaceutical problem is designing diverse and selective lead compounds. The human genome sequence provides opportunities to discover compounds that are protein selective if we can develop methods to identify specificity determinants from sequence alone. We have analyzed sequence and structural diversity of sheep COX-1 and mouse COX-2 proteins by Active Site Profiling (ASP). Eleven residues that should serve as specificity determinants between COX-1 and COX-2 were identified; however, the literature suggests that only one has been utilized in structure-based discovery. ASP was used to create a position-specific scoring matrix, which was used to identify possible cross-reacting proteins from the human sequences. This method proved selective for cyclooxygenases, comparing well with results using BLAST. The methods identify a probable misannotation of a cyclooxygenase in which there is high sequence similarity scores using BLAST, but ASP shows it does not contain the residues necessary for cyclooxygenase function. ASP Analysis of human COX proteins suggests that some specificity determinants that distinguish COX-1 and COX-2 proteins are similar between sheep COX-1/mouse COX-2 and human COX-1/COX2; however, residue identities at those positions are not necessarily conserved. Our results lay groundwork for development of family-specific pattern recognition methods to selectively match compounds with proteins.

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Active Site Profiling to Identify Protein Functional Sites in Sequences and Structures Using the Deacon Active Site Profiler (DASP)

Fetrow

2006

CP in Bioinformatics

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Methods for the annotation and analysis of functional sites in proteins are an area of active research, and those methods that allow detailed characterization of functional site features are much needed. A Web site application, DASP, which implements a previously described method (Cammer, et al., 2003) to allow users to create an active site profile for any protein family, is described. Two protocols for functional site analysis of protein families using DASP are presented: 1) creation of functional site signatures and a profile from proteins of known structure and 2) utilization of the active site profile to search sequences that contain fragments similar to those found in the functional site signatures. The active site profile produced by Basic Protocol 1 allows the user to analyze the features of the functional site, i.e., those characteristics that are common across the family and those that are unique to one or several members of the family. The characteristics that are unique to a subfamily might be described as specificity determinants i.e., features that impart specificity to a particular function. Basic Protocol 2 provides instructions for searching for sequences that might contain a similar functional site.

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Structure-based Active Site Profiles for Genome Analysis and Functional Family Subclassification

Cited by 53 publications

References 51 publications

Comparison of protein active site structures for functional annotation of proteins and drug design

Comparison of protein active site structures for functional annotation of proteins and drug design

Chemical and Structural Diversity in Cyclooxygenase Protein Active Sites

Active Site Profiling to Identify Protein Functional Sites in Sequences and Structures Using the Deacon Active Site Profiler (DASP)

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