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PDBsum entry 3nx7
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Crystal structure of the catalytic domain of human mmp12 complexed with the inhibitor n-hydroxy-2-(n-(2-hydroxyethyl)4- methoxyphenylsulfonamido)acetamide
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Structure:
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Macrophage metalloelastase. Chain: a. Fragment: catalytic domain (unp residues 106 to 263). Synonym: mme, matrix metalloproteinase-12, mmp-12, macrophage elastase, me, hme. 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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1.80Å
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R-factor:
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0.166
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R-free:
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0.200
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Authors:
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I.Bertini,V.Calderone,M.Fragai,A.Giachetti,M.Loconte,C.Luchinat, M.Maletta,C.Nativi,K.J.Yeo
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Key ref:
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I.Bertini
et al.
(2007).
Exploring the subtleties of drug-receptor interactions: the case of matrix metalloproteinases.
J Am Chem Soc,
129,
2466-2475.
PubMed id:
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Date:
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13-Jul-10
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Release date:
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28-Jul-10
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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.
158 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 1 residue position (black
cross)
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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 Am Chem Soc
129:2466-2475
(2007)
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PubMed id:
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Exploring the subtleties of drug-receptor interactions: the case of matrix metalloproteinases.
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I.Bertini,
V.Calderone,
M.Fragai,
A.Giachetti,
M.Loconte,
C.Luchinat,
M.Maletta,
C.Nativi,
K.J.Yeo.
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ABSTRACT
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By solving high-resolution crystal structures of a large number (14 in this
case) of adducts of matrix metalloproteinase 12 (MMP12) with strong, nanomolar,
inhibitors all derived from a single ligand scaffold, it is shown that the
energetics of the ligand-protein interactions can be accounted for directly from
the structures to a level of detail that allows us to rationalize for the
differential binding affinity between pairs of closely related ligands. In each
case, variations in binding affinities can be traced back to slight improvements
or worsening of specific interactions with the protein of one or more ligand
atoms. Isothermal calorimetry measurements show that the binding of this class
of MMP inhibitors is largely enthalpy driven, but a favorable entropic
contribution is always present. The binding enthalpy of acetohydroxamic acid
(AHA), the prototype zinc-binding group in MMP drug discovery, has been also
accurately measured. In principle, this research permits the planning of either
improved inhibitors, or inhibitors with improved selectivity for one or another
MMP. The present analysis is applicable to any drug target for which structural
information on adducts with a series of homologous ligands can be obtained,
while structural information obtained from in silico docking is probably not
accurate enough for this type of study.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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M.Rouffet,
C.Denhez,
E.Bourguet,
F.Bohr,
and
D.Guillaume
(2009).
In silico study of MMP inhibition.
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Org Biomol Chem,
7,
3817-3825.
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F.E.Jacobsen,
M.W.Buczynski,
E.A.Dennis,
and
S.M.Cohen
(2008).
A macrophage cell model for selective metalloproteinase inhibitor design.
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Chembiochem,
9,
2087-2095.
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M.Pellecchia,
I.Bertini,
D.Cowburn,
C.Dalvit,
E.Giralt,
W.Jahnke,
T.L.James,
S.W.Homans,
H.Kessler,
C.Luchinat,
B.Meyer,
H.Oschkinat,
J.Peng,
H.Schwalbe,
and
G.Siegal
(2008).
Perspectives on NMR in drug discovery: a technique comes of age.
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Nat Rev Drug Discov,
7,
738-745.
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R.Bhaskaran,
M.O.Palmier,
J.L.Lauer-Fields,
G.B.Fields,
and
S.R.Van Doren
(2008).
MMP-12 catalytic domain recognizes triple helical peptide models of collagen V with exosites and high activity.
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J Biol Chem,
283,
21779-21788.
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L.A.Alcaraz,
L.Banci,
I.Bertini,
F.Cantini,
A.Donaire,
and
L.Gonnelli
(2007).
Matrix metalloproteinase-inhibitor interaction: the solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors.
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J Biol Inorg Chem,
12,
1197-1206.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
