From Protein Structure to Function with Bioinformatics.pdf

10 Integrated Servers for Structure-Informed Function Prediction 26310.3.1.5 Template MethodsThe final ProFunc methods involve four different types of residue template searches(Laskowski et al. 2005c). The templates are defined as specific 3D conformationsof, typically, three amino acid residues. The template searches are carried out by afast 3D search algorithm called JESS (Barker and Thornton 2003), performed inparallel on the processor farm.Enzyme TemplatesThe first group of templates are the enzyme active site templates which come fromthe manually compiled Catalytic Site Atlas (CSA) (Porter et al. 2004). Here eachtemplate consists of two to five residues that are identified in the literature as beingcatalytic or are highly-conserved residues in the neighbourhood of the catalyticresidues. A strong match (see below) to one of these templates can be highly suggestiveof the protein’s function.Ligand- and DNA-Binding TemplatesThe next two groups of templates are the ligand- and DNA-binding templates.These are automatically generated once a week so as to be as up-to-date as thePDB. The ligand templates are generated by considering in turn every type of HetGroup (as defined in the PDB’s Het Group Dictionary) and retrieving a non-homologouslist of structures in the PDB that contain this Het Group. Residues interactingwith the Het Group in each selected structure are marked. The templates, consistingof groups of three residues from each structure’s marked residues, are saved astemplates for that Het Group. The selection criteria governing which groups ofthree residues can form a template are as follows: each of the residues must bewithin 5 Å of one of the others in the template, each template can have at most onehydrophobic residue (i.e. Ala, Phe, Ile, Leu, Met, Pro or Val) – this is to bias thetemplates towards surface residues – and no two templates from the same structurecan have more than one residue in common. The order in which the potential templatesare considered is biased by their relative importance. Thus a template containingresidues that make several hydrogen bonds to the given Het Group are morehighly valued than those whose residues only interact with the Het Group via asmall number of non-bonded contacts.The DNA-binding templates are generated in exactly the same way except thatall DNA and RNA molecules are treated as though they were a single Het Group.As of May 2008, there were 584 CSA templates, 97,534 ligand-binding templatesand 3,390 DNA-binding templates in these template databases.Figure 10.6 shows a template match in 2fck to a coA ligand-binding template takenfrom PDB entry 1s7n, a RimL N(α)-acetyltransferase from Salmonella typhimurium.