Reliable assignment of function to enzymes discovered in genome sequencing projects is a major challenge in genomic biology. I will discuss the use of computational ligand docking and protein homology modeling, by our group and others, to help guide investigations of enzyme-substrate specificity, and the identification of novel enzymatic functions. Our group has used the functionally diverse enolase superfamily as a model system for testing approaches to exploiting structure to predict enzyme substrates, in a series of retrospective and prospective studies. At this point, we have studied hundreds of enzymes in this superfamily using computational approaches, providing insight into the sequence and structural determinants of specificity. Enzymatic assays (group of John Gerlt, UIUC) and crystallography (group of Steve Almo, Albert Einstein College of Medicine) have confirmed a number of the prospective predictions. Finally, I will discuss the strengths, weaknesses, and future prospects for this type of “structure-based” approach to investigating protein function, and the complementarity with “sequence-based” methods. |
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