A NEW SERINE PROTEASE FOLD REVEALED BY THE CRYSTAL STRUCTURE OF HUMAN CYTOMEGALOVIRUS PROTEASE. L. Tong¹, C. Qian¹, M.-J. Massariol², P.R. Bonneau², M.G. Cordingley², L. Lagacé², ¹Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, ²Bio-Méga/Boehringer Ingelheim Research, Inc., 2100 rue Cunard, Laval, Québec, Canada H7S 2G5

A new polypeptide backbone fold for serine proteases has been identified based on the crystal structure of human cytomegalovirus protease. The structure was determined at 2.5Å resolution by the multiple-wavelength anomalous diffraction technique using the seleno-methionyl protein and refined at 2.0Å resolution. It reveals a seven-stranded mostly-antiparallel ß-barrel, which is surrounded by seven helices. The active site residues (Ser-132 and His-63) are situated on the outside of the ß-barrel and in a groove on the surface of the protein. The structure suggests that the third member of the catalytic triad is probably His-157. The protease of herpesviruses plays an essential role in the production of infectious virions and is an attractive target for the developement of anti-herpes agents. The crystal structure information will help in the design and optimization of inhibitors against herpesvirus protease.

[1] Tong, L., Qian, C., Massariol, M.-J., Bonneau, P.R., Cordingley, M.G. & Lagacé, L. Nature, submitted.