Crystallographic study of a beta-lactam inhibitor complex with elastase at 1.84 A resolution.
The continuing discovery and development of beta-lactams as antibiotics has had an unparalleled impact on the overall health and well-being of society. Recently, appropriately substituted cephalosporins were shown to be potent inhibitors of elastase, suggesting a novel therapeutic role for the beta-lactams in the control of emphysema and other degenerative diseases. We have now solved and partially refined at atomic resolution the structure of a complex of porcine pancreatic elastase with the time-dependent irreversible inhibitor 3-acetoxymethyl-7-alpha-chloro-3-cephem-4-carboxylate-1,1-dioxide tert-butyl ester (I), the most potent of the beta-lactam elastase inhibitors yet reported. (Porcine pancreatic elastase is a close relative of the desired drug target, human polymorphonuclear leukocyte elastase.) A mechanism of action is presented, based on the structure and on biochemical evidence (T.-Y.L. et al., in preparation), which clarifies the operational similarities and differences between beta-lactam elastase inhibitors and antibiotics. Features of the reaction include the expulsion of a leaving group at the cephalosporin 3' position and the formation of two covalent bonds with the active site of porcine pancreatic elastase at residues Ser 195 and His 57.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D007769:Lactams; D008958:Models, Molecular; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013552:Swine; D014961:X-Ray Diffraction; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D007769:Lactams; D047090:beta-Lactams; C052412:3-acetoxymethyl-7-chloro-3-cephem-4-carboxylate-1,1-dioxide tert-butylester; D010196:Pancreatic Elastase