X-Ray Crystallography Program

Bugg, Charles

Abstract

The objective of the crystallography program is to use the techniques of protein crystallography to determine the three-dimensional structures of calcium-binding proteins, and of enzymes that are targets for inhibitor design. The structures of calcium-binding proteins will be used to obtain more information about the factors that are involved in calcium interactions with protein-binding sites, and to better understand the structure/function relationships of calcium in biological systems. The crystallographic studies of target enzymes is being used to guide the synthesis of compounds that are designed to block the active sites on these proteins. We have recently determined the 3 angstrom structures of calmodulin and pea lectin, which are two calcium-binding proteins. Efforts to refine these structures, and to examine the structures of various complexes with these proteins are in progress. Crystallographic studies of C-reactive protein, a calcium-dependent protein of the immune system, are now being pursued at low resolution, and future plans include a high-resolution analysis of this protein. We have now completed the 3 angstrom crystallographic analysis of human erythrocytic purine nucleoside phosphorylase (PNP). PNP is of particular interest as an inhibitor design target, since this enzyme is required for the activity of T-cells, but not of B-cells. Consequently, an inhibitor of PNP may prove to be an important T-cell specific immunosuppressive agent. Current efforts are in progress to use the detailed information about the PNP structure to guide the synthesis of compounds that are tailored to fit the active site of the enzyme.