to Protein Structure and Function
Gallery of 150 Thermotoga maritima structures solved by lab and JCSG.
Evaluating protein structure and function is of primary importance for understanding the basic biology of the cell and is a challenge in the context of the constantly expanding wealth of genomic information.
We have been analyzing protein structures as part of the Protein Structure Initiative since its inception in 2000. We have established high-throughput approaches to evaluating structural and functional diversity of proteins to address this challenge part of a structural genomics effort with the Joint Center for Structural Genomics (JCSG).
Our goal is to develop a high-throughput and cost-effective structure pipeline and to utilize it to determine novel protein folds and to explore protein structure/function relationships.
Our approach comprises: a bioinformatic platform to analyze gene relationships and propose putative functions for testing, utilization of an existing high-throughput platform for producing thousands of proteins in milligram quantities for analysis, ligand screening technologies combined with metabolite-focused compound libraries to define specificity profiles of enzymes, and focused experimental validation of proposed functions of key target genes and pathways.
We apply these same high-throughput tools to characterize the molecular basis of enzyme substrate specificity.
To understand how genome sequences relate to the biology of the organism, correct annotation of gene function is essential. There are many computational approaches to assigning a putative gene function based on similarity to known activities. However, as the evolutionary distances extend and the number of putative homologs expands, the reliability of such unvalidated predictions becomes suspect. Likewise, while enzyme classes and broad activities may be predicted with some certainty, much less can be inferred regarding substrate specificity. This specificity defines the role of that enzyme at a functional level and understanding enzyme selectivity is essential to understanding the enzyme in the biology of the organism.