Document Detail

Molecular determinants of a selective matrix metalloprotease-12 inhibitor: Insights from crystallography and thermodynamic studies.
MedLine Citation:
PMID:  23343195     Owner:  NLM     Status:  Publisher    
The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor towards matrix metalloprotease-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 Å) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P1' side chain filling most part of the S1' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (ΔG°= -13.1 kcal/mol, ΔH°= -2.53 kcal/mol and -TΔS°= -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.
Bertrand Czarny; Enrico A Stura; Laurent Devel; Laura Vera; Evelyne Lajeunesse; Fabrice Beau; Vito Calderone; Marco Fragai; Claudio Luchinat; Vincent Dive
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-23
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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