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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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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of the catalytic domain of human mmp12 in complex with selective phosphinic inhibitor rxp470.1
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Structure:
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Macrophage metalloelastase. Chain: a. Fragment: catalytic domain (unp residues 106-263). Synonym: mme, macrophage elastase, me, hme, matrix metalloproteinase- 12, mmp-12. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: hme, mmp12. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.15Å
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R-factor:
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0.134
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R-free:
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0.155
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Authors:
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E.A.Stura,L.Vera,F.Beau,L.Devel,E.Cassar-Lajeunesse,V.Dive
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Key ref:
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B.Czarny
et al.
(2013).
Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies.
J Med Chem,
56,
1149-1159.
PubMed id:
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Date:
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23-Aug-12
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Release date:
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06-Feb-13
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PROCHECK
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Headers
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References
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P39900
(MMP12_HUMAN) -
Macrophage metalloelastase from Homo sapiens
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Seq:
Struc:
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470 a.a.
159 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.3.4.24.65
- macrophage elastase.
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Reaction:
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Hydrolysis of soluble and insoluble elastin. Specific cleavages are also produced at 14-Ala-|-Leu-15 and 16-Tyr-|-Leu-17 in the B chain of insulin.
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Cofactor:
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Ca(2+); Zn(2+)
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J Med Chem
56:1149-1159
(2013)
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PubMed id:
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Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies.
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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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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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