From Protein Structure to Function with Bioinformatics.pdf

212 E.C. Meng et al.8.6 DiscussionA rationale for using 3D motifs over fold comparisons is that the structural featuresdirectly involved in a function should serve as the most precise and effective signatureof that function. It is more difficult, however, to determine which residues aretruly important for a function than to use the entire fold. Although mere proximityto a catalytic or binding site is strongly suggestive of a residue’s importance, it isan imperfect indicator. As more structures are solved, however, methods thatextract motifs from diverse sets of positive examples are becoming more viable.That approach shifts the burden from the direct identification of residues to theselection of appropriate sets of structures to represent functions.What is the most natural classification of proteins from the perspective ofthese “fine structure” 3D motifs? In enzymes, individual residues or functionalgroups play different roles in the course of a reaction: substrate recognition,catalysis of a particular step in the reaction, stabilization of an intermediate, orsome combination of these. To complicate matters, as proteins evolve to performnew functions, they can make use of existing local structural features that contributethe same partial function to both the new and old functions (Babbitt and Gerlt2000; Bartlett et al. 2003). This explains in part why members of a homologousbut diverse group of enzymes often make use of the same configuration of a smallnumber of amino acids, despite catalyzing different overall reactions. Forenzymes, one can imagine a hierarchy of motifs, including patterns associatedwith sub-functions shared among all members of a divergent group and largerpatterns correlated with the overall reaction catalyzed by members of a moreclosely related set. A natural classification would then include a tier for homologousgroups known to share a sub-function, with specific structural features (a 3Dmotif) associated with that sub-function (Babbitt 2003). It may be possible todescribe small-molecule binding functions in a similar way, with ligand substructuresserving in an analogous role to that served by partial reactions; furthermore,binding is rarely a complete description of function, and additional elements ofstructure may be associated with conformational changes or recognition of othermolecules upon ligand binding.The difficulty in generating such structure-based functional classificationsillustrates the need for obtaining more detailed information on structures andenzymatic mechanisms to identify which sub-functions are more conservedthrough evolution than others.8.7 ConclusionsThree-dimensional motifs are patterns of local structure usually associated withfunction, typically based on residues in binding or catalytic sites. Over evolutionarytime, proteins can diverge by the accumulation of random changes thatdo not change function, but retain structural components critical to that function.