X-ray Snapshot of the Mechanism of Inactivation of Human Neutrophil Elastase by 1,2,5-Thiadiazolidin-3-one 1,1-Dioxide Derivatives

• Published in: Journal of medicinal chemistry 2008-04, Vol.51 (7), p.2003-2008
• Main Authors: Huang, Weijun, Yamamoto, Yasufumi, Li, Yi, Dou, Dengfeng, Alliston, Kevin R, Hanzlik, Robert P, Williams, Todd D, Groutas, William C
• Format: Article
• Language: English
• Subjects: Binding Sites - drug effects; Biological and medical sciences; Crystallography, X-Ray; Cyclic S-Oxides - chemical synthesis; Cyclic S-Oxides - chemistry; Cyclic S-Oxides - pharmacology; Enzyme Activation - drug effects; Humans; Leukocyte Elastase - antagonists & inhibitors; Leukocyte Elastase - chemistry; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Protein Structure, Tertiary; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm700966p

The mechanism of action of a general class of mechanism-based inhibitors of serine proteases, including human neutrophil elastase (HNE), has been elucidated by determining the X-ray crystal structure of an enzyme–inhibitor complex. The captured intermediate indicates that processing of inhibitor by the enzyme generates an N-sulfonyl imine functionality that is tethered to Ser195, in accordance with the postulated mechanism of action of this class of inhibitors. The identity of the HNE-N-sulfonyl imine species was further corroborated using electrospray ionization mass spectrometry.