From Protein Structure to Function with Bioinformatics.pdf

8 3D Motifs 203In addition to SITE motifs, the PDBSite database (Ivanisenko et al. 2005) (Table8.1) includes interaction sites with other proteins, RNA, and DNA. Residues withat least three atoms within 5 Å of the other chain are included in an interaction site.All or a subset of the sites in the database can be compared to a structure of interestwith PDBSiteScan (Ivanisenko et al. 2004) (Table 8.1), which uses residue types,backbone atom positions, and user-specified cutoffs. A superposition of the querystructure and matching 3D motifs can be downloaded in PDB format.The program RIGOR is essentially the same as SPASM, except designed for theinverse process: comparing a structure to a database of 3D motifs instead of comparinga motif to a database of structures (Kleywegt 1999). RIGOR executables andthe associated database of motifs are available for download from the UppsalaSoftware Factory (Table 8.2). The database includes sites around bound ligands,stretches of consecutive identical residues, and certain other residue clusters. Eachligand site is included twice, with and without residues labelled by type. Matchesto a motif unlabelled by residue type may suggest that the query structure could beengineered to contain such a site.3D-motif searches are central to function predictions made by two servers thatintegrate the results produced with other data. These servers are discussed in detailin Chapter 11 but are briefly mentioned here for completeness. The ProKnowserver (Pal and Eisenberg 2005) (Table 8.1) performs multiple sequence- and structure-basedsearches with a single query, including a RIGOR search of 3D motifsfrom individual structures. Each database searched by ProKnow includes GO annotations,and the end result is a list of possible GO annotations for the query and theirBayesian scores (estimated probabilities). However, many of the GO terms are verygeneral. The second integrated method, the ProFunc server (Laskowski et al.2005b) (Table 8.1) also performs multiple sequence- and structure-based searches.JESS (Barker and Thornton 2003) is used to search enzyme active site templatesfrom the CSA and triplets of ligand- or nucleic acid-binding residues from a nonredundantsubset of the PDB. To provide more thorough coverage of structure space,a “reverse template” search is also performed, where the query is broken up into 3Dmotifs that are compared to a representative set of whole structures from the PDB(Laskowski et al. 2005a). JESS hits are further evaluated by expanding the comparisonto a 10Å-radius sphere centred on the matched motif. Matches are rankedwith a score that favours overlaid pairs of residues of similar types with similarsequence spacing and order. Thus, the motif search is made more specific but alsoless local and consequently less likely to identify examples of convergent evolution.Each motif is (or has been) scanned against a sample of structures from the PDB,and E-values are computed assuming an extreme value distribution of scores(Laskowski et al. 2005a).The SuMo server (Jambon et al. 2005) (Table 8.1) compares a query structure toeither a “PDB full structures” database (all entries but with redundant chains withinan entry removed) or just the ligand-binding sites from that database. The query canbe an entire structure, a chain, or a ligand-binding site. SuMo represents structuresas graphs of triangles of chemical groups, which include various hydrogen bonddonors and acceptors, aromatic rings, etc. (Jambon et al. 2003). When two structures