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PDBsum entry 1d8f
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Contents |
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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 mmp3 complexed with a piperazine based inhibitor.
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Structure:
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Stromelysin-1 precursor. Chain: a, b. Fragment: catalytic domain. Synonym: mmp-3. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Cell: fibroblast. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.40Å
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R-factor:
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0.294
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R-free:
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0.252
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Authors:
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M.Y.Cheng,B.De,S.Pikul,N.G.Almstead,M.G.Natchus,M.V.Anastasio, S.J.Mcphail,C.E.Snider,Y.O.Taiwo,L.Y.Chen
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Key ref:
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M.Cheng
et al.
(2000).
Design and synthesis of piperazine-based matrix metalloproteinase inhibitors.
J Med Chem,
43,
369-380.
PubMed id:
DOI:
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Date:
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22-Oct-99
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Release date:
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23-Oct-00
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PROCHECK
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Headers
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References
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P08254
(MMP3_HUMAN) -
Stromelysin-1 from Homo sapiens
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Seq:
Struc:
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477 a.a.
169 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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Enzyme class:
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E.C.3.4.24.17
- stromelysin 1.
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Reaction:
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Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
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Cofactor:
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Ca(2+); Zn(2+)
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DOI no:
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J Med Chem
43:369-380
(2000)
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PubMed id:
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Design and synthesis of piperazine-based matrix metalloproteinase inhibitors.
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M.Cheng,
B.De,
S.Pikul,
N.G.Almstead,
M.G.Natchus,
M.V.Anastasio,
S.J.McPhail,
C.E.Snider,
Y.O.Taiwo,
L.Chen,
C.M.Dunaway,
F.Gu,
M.E.Dowty,
G.E.Mieling,
M.J.Janusz,
S.Wang-Weigand.
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ABSTRACT
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A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived
from dl-piperazinecarboxylic acid has been described. The design involves:
incorporation of hydroxamic acid as the bidentate chelating agent for catalytic
Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine
ring to fill the S1' pocket of the enzyme, and finally attachment of diverse
functional groups at the 4N-position to optimize potency and peroral absorption.
A unique combination of all three elements produced inhibitor 20 with high
affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray
crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed
information on key binding interactions defining an overall scaffold geometry
for piperazine-based MMP inhibitors.
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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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X.Chen,
S.Dong,
Z.Qiao,
Y.Zhu,
M.Xie,
L.Lin,
X.Liu,
and
X.Feng
(2011).
Guanidine Organocatalyst for the Asymmetric Mannich-Type Reaction between α-Isothiocyanato Imide and Sulfonyl Imines.
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Chemistry,
17,
2583-2586.
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A.Rolfe,
G.H.Lushington,
and
P.R.Hanson
(2010).
Reagent based DOS: a "Click, Click, Cyclize" strategy to probe chemical space.
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Org Biomol Chem,
8,
2198-2203.
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P.Storz,
H.Döppler,
J.A.Copland,
K.J.Simpson,
and
A.Toker
(2009).
FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases.
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Mol Cell Biol,
29,
4906-4917.
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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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M.Kontoyianni,
G.S.Sokol,
and
L.M.McClellan
(2005).
Evaluation of library ranking efficacy in virtual screening.
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J Comput Chem,
26,
11-22.
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M.A.Rudek,
J.Venitz,
and
W.D.Figg
(2002).
Matrix metalloproteinase inhibitors: do they have a place in anticancer therapy?
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Pharmacotherapy,
22,
705-720.
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P.J.Gane,
and
P.M.Dean
(2000).
Recent advances in structure-based rational drug design.
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Curr Opin Struct Biol,
10,
401-404.
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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
