X-ray snapshot of the mechanism of inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives

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Authors
Huang, Weijun
Yamamoto, Yasufumi
Li, Yi
Dou, Dengfeng
Alliston, Kevin R.
Hanzlik, Robert P.
Williams, Todd D.
Groutas, William C.
Issue Date
2008-04-10
Type
Article
Language
eng
Keywords
Research Support, N.I.H., Extramural , Research Support, Non-U.S. Gov't , Research Support, U.S. Gov't, Non-P.H.S.
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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.

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Citation
Journal of medicinal chemistry. 2008 Apr 10; 51(7): 2003-8.
Publisher
American Chemical Society
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ISSN
0022-2623
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