Structure of human neutrophil elastase in complex with a peptide chloromethyl ketone inhibitor at 1.84-A resolution

• Published in: Proceedings of the National Academy of Sciences - PNAS 1989-01, Vol.86 (1), p.7-11
• Main Authors: NAVIA, M. A, MCKEEVER, B. M, SPRINGER, J. P, TSAU-YEN LIN, WILLIAMS, H. R, FLUDER, E. M, DORN, C. P, HOOGSTEEN, K
• Format: Article
• Language: English
• Subjects: Amino Acid Chloromethyl Ketones - metabolism; Binding Sites; Biological and medical sciences; Crystalline structure; Fundamental and applied biological sciences. Psychology; Humans; Models, Molecular; Molecular biophysics; Neutrophils - enzymology; Pancreatic Elastase - antagonists & inhibitors; Pancreatic Elastase - blood; Protein Binding; Protein Conformation; Sputum - enzymology; Structure in molecular biology; X-Ray Diffraction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.86.1.7

Human neutrophil elastase (HNE) has been implicated as a major contributor to tissue destruction in various disease states, including emphysema. The structure of HNE, at neutral pH, in complex with methoxysuccinyl-Ala-Ala-Pro-Ala chloromethyl ketone (MSACK), has been solved and refined to an R factor of 16.4% at 1.84-A resolution. Results are consistent with the currently accepted mechanism of peptide chloromethyl ketone inhibition of serine proteases, in that MSACK cross-links the catalytic residues His-57 and Ser-195. The structure of the HNE-MSACK complex is compared with that of porcine pancreatic elastase in complex with L-647,957, a beta-lactam inhibitor of both elastases. The distribution of positively charged residues on HNE is highly asymmetric and may play a role in its specific association with the underlying negatively charged proteoglycan matrix of the neutrophil granules in which the enzyme is stored.