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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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Department of Chemistry, Wichita State University, Wichita, Kansas 67260, Protein Structure Laboratory, The University of Kansas, Lawrence, Kansas 66047, and Mass Spectrometry Lab, The University of Kansas, Lawrence, Kansas 66047
* To whom correspondence should be addressed. Tel.: (316) 978 7374 . Fax: (316) 978 3431. E-mail: [email protected].
§Protein Structure Laboratory, The University of Kansas.
‡Wichita State University.
∥Mass Spectrometry Lab, The University of Kansas.
†Coordinates of the HNE-inhibitor(I) complex have been deposited in the Protein Data Bank with the access code of 2RG3.
Cite this: J. Med. Chem. 2008, 51, 7, 2003–2008
Publication Date (Web):March 5, 2008
https://doi.org/10.1021/jm700966p
Copyright © 2008 American Chemical Society

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    Abstract

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    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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