W0457

New approaches are required to fully exploit and leverage the utility of on-going Functional and Structural Genomics Programs. A protein structure immediately allows for the identification of conserved solvent accessible features that represent the biologically important surfaces, including protein-ligand binding sites, active sites and effector-binding sites. This structural information provides a unique opportunity for the rational construction of conditional mutants (e.g., temperature sensitive) and the identification of their extragenic suppressors. The discovery of these conditional mutant/suppressor pairs represents a powerful and unbiased approach for the identification of interacting proteins and offers a novel scheme for the dissection of function and mechanism with unprecedented detail. The success of Structural Genomics promises to reshape structural biology in another important respect. In particular, as the structures of unique folds and individual domains continue to accrue, there must be a deliberate and concerted shift towards the examination of multi-component assemblies, which are the true operational units of biological function. This shift in focus is essential as individual gene products rarely function independently, and it is typically large multi-component protein complexes that are the ultimate effectors of complex cellular functions. Accordingly, one of the outstanding challenges in the post genomics era is the quantitative description of the regulatory circuits that control the spatial and temporal assembly, organization and function of these complex biological machines. The infrastructure of the Structural Genomics movement is now providing the basis for a concerted National effort to examine the multi-component biological machines responsible for complex biological processes.