Crystallographic Study of a (beta)-lactam Inhibitor Complex with Elastase at 1.84 A Resolution

• Published in: Nature (London) 1987-05, Vol.327 (6117), p.79-79
• Main Authors: Navia, Manuel A, Springer, James P, Tsau-Yen, Lin, Williams, Hollis R, Fi restone, Raymond A
• Format: Article
• Language: English
• Subjects: Antibiotics; Biochemistry; Inhibitors; Medical research
• ISSN: 0028-0836; 1476-4687

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.