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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites / drug effects
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Crystallography, X-Ray
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Cyclic S-Oxides / chemical synthesis
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Cyclic S-Oxides / chemistry*
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Cyclic S-Oxides / pharmacology*
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Enzyme Activation / drug effects
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Humans
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Leukocyte Elastase / antagonists & inhibitors*
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Leukocyte Elastase / chemistry*
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Models, Molecular
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Molecular Structure
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Protein Structure, Tertiary
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Serine Proteinase Inhibitors / chemical synthesis
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Serine Proteinase Inhibitors / chemistry*
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry*
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Thiazoles / pharmacology*
Substances
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1,2,5-thiadiazolidin-3-one 1,1-dioxide
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Cyclic S-Oxides
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Serine Proteinase Inhibitors
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Thiazoles
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Leukocyte Elastase