The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor toward matrix metal-loprotease-12 (MMP-12) remain elusive. To address this issue, structure-activity study, X-ray crystallography, and isothermal titration calorimetry (ITC) experiments were performed. The crystal structure of MMP-12/inhibitor complex (1.15 angstrom) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P-1' side chain filling most of the S-1' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (Delta G degrees = 13.1 kcal/mol, Delta H degrees = -2.53 kcal/mol, and -T Delta S degrees = -10.60 kcal/mol) and involves a proton uptake from the buffer. Comparing phosphinic versus hydroxamate inhibitors reveals that the chelation of the zinc ion is slightly different, leading the inhibitor backbone to adopt a position in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhibitor while maintaining high affinity.
Molecular Determinants of a Selective Matrix Metalloprotease-12 Inhibitor: Insights from Crystallography and Thermodynamic Studies / Bertrand Czarny;Enrico A. Stura;Laurent Devel;Laura Vera;Evelyne Cassar-Lajeunesse;Fabrice Beau;Vito Calderone;Marco Fragai;Claudio Luchinat;Vincent Dive. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 1149-1159. [10.1021/jm301574d]
Molecular Determinants of a Selective Matrix Metalloprotease-12 Inhibitor: Insights from Crystallography and Thermodynamic Studies
CALDERONE, VITO;FRAGAI, MARCO;LUCHINAT, CLAUDIO;
2013
Abstract
The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor toward matrix metal-loprotease-12 (MMP-12) remain elusive. To address this issue, structure-activity study, X-ray crystallography, and isothermal titration calorimetry (ITC) experiments were performed. The crystal structure of MMP-12/inhibitor complex (1.15 angstrom) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P-1' side chain filling most of the S-1' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (Delta G degrees = 13.1 kcal/mol, Delta H degrees = -2.53 kcal/mol, and -T Delta S degrees = -10.60 kcal/mol) and involves a proton uptake from the buffer. Comparing phosphinic versus hydroxamate inhibitors reveals that the chelation of the zinc ion is slightly different, leading the inhibitor backbone to adopt a position in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhibitor while maintaining high affinity.File | Dimensione | Formato | |
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