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PDBsum entry 4gql
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Hydrolase/hydrolase inhibitor
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PDB id
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4gql
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References listed in PDB file
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Key reference
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Title
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Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies.
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Authors
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B.Czarny,
E.A.Stura,
L.Devel,
L.Vera,
E.Cassar-Lajeunesse,
F.Beau,
V.Calderone,
M.Fragai,
C.Luchinat,
V.Dive.
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Ref.
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J Med Chem, 2013,
56,
1149-1159.
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PubMed id
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Abstract
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The molecular determinants responsible for the potency of the RXP470.1
phosphinic peptide inhibitor toward 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 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
(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.
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