title: X-ray snapshot of the mechanism of inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives.
abstract: 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.
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Weijun
authors.initials: W
authors.lastname: Huang
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Dengfeng
authors.initials: D
authors.lastname: Dou
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Alliston
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hanzlik
authors.forename: Todd D
authors.initials: TD
authors.lastname: Williams
authors.forename: William C
authors.initials: WC
authors.lastname: Groutas
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C428430:1,2,5-thiadiazolidin-3-one 1,1-dioxide; D003499:Cyclic S-Oxides; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D019272:Leukocyte Elastase