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A substrate variant as a high-affinity, reversible inhibitor: insight from the X-ray structure of cilastatin bound to membrane dipeptidase.
Smyth, Timothy P; Wall, J Gerard; Nitanai, Yasushi.
Afiliação
  • Smyth TP; Department of Chemical and Environmental Sciences, Univeristy of Limerick, National Technological Park, County Limerick, Ireland. timothy.smyth@ul.ie
Bioorg Med Chem ; 11(6): 991-8, 2003 Mar 20.
Article em En | MEDLINE | ID: mdl-12614884
ABSTRACT
An analysis of the X-ray structure of cilastatin bound to membrane dipeptidase, together with docking studies, is presented here to reveal how a simple amide may act as a high-affinity, reversible, amidase inhibitor. Cilastatin binds as a normal substrate and is orientated in a perfect near-attack conformer for formation of a tetrahedral intermediate with the zinc-bound water/hydroxide. This intermediate is fated, however, only to revert to its starting components as scission of the amide bond is prevented by the precise fit of cilastatin within the active site. The cilastatin alkyl end groups that are tightly buttressed against amino acid residues on opposite sides of the active site, are aligned along the C-N reaction coordinate axis thereby preventing collapse of the intermediate via rupture of the C-N bond. Such a feature could have more general applicability in the explicit design of substrate variants as selective, tight-binding, and reversible inhibitors.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cilastatina / Dipeptidases Idioma: En Ano de publicação: 2003 Tipo de documento: Article
Buscar no Google
Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cilastatina / Dipeptidases Idioma: En Ano de publicação: 2003 Tipo de documento: Article