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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.


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.

SUBMITTER: Huang W 

PROVIDER: S-EPMC3623276 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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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.

Huang Weijun W   Yamamoto Yasufumi Y   Li Yi Y   Dou Dengfeng D   Alliston Kevin R KR   Hanzlik Robert P RP   Williams Todd D TD   Groutas William C WC  

Journal of medicinal chemistry 20080305 7


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  ...[more]

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