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* Residue conservation analysis
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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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Calcium; Zinc
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Gene Ontology (GO) functional annotation
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Cellular component
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extracellular matrix
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1 term
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Biological process
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proteolysis
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1 term
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Biochemical function
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metallopeptidase activity
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3 terms
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DOI no:
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J Med Chem
40:1026-1040
(1997)
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PubMed id:
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Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.
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C.K.Esser,
R.L.Bugianesi,
C.G.Caldwell,
K.T.Chapman,
P.L.Durette,
N.N.Girotra,
I.E.Kopka,
T.J.Lanza,
D.A.Levorse,
M.MacCoss,
K.A.Owens,
M.M.Ponpipom,
J.P.Simeone,
R.K.Harrison,
L.Niedzwiecki,
J.W.Becker,
A.I.Marcy,
M.G.Axel,
A.J.Christen,
J.McDonnell,
V.L.Moore,
J.M.Olszewski,
C.Saphos,
D.M.Visco,
W.K.Hagmann.
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ABSTRACT
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Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position
were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A
(MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1).
Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a
methyl group at P3' produced orally bioavailable inhibitors as measured by an in
vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural
cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the
catalytic domain of MMP-3 is described. Inhibitors that contained halogenated
biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency
and oral activity with
2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid
1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of
10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity
assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in
the rabbit) and chronic (rat adjuvant-induced arthritis and mouse
collagen-induced arthritis) models of cartilage destruction but showed activity
only in the MMP-3 injection model (ED50 = 6 mg/kg iv).
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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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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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V.Lukacova,
Y.Zhang,
M.Mackov,
P.Baricic,
S.Raha,
J.A.Calvo,
and
S.Balaz
(2004).
Similarity of binding sites of human matrix metalloproteinases.
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J Biol Chem, 279,
14194-14200.
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P.A.Elkins,
Y.S.Ho,
W.W.Smith,
C.A.Janson,
K.J.D'Alessio,
M.S.McQueney,
M.D.Cummings,
and
A.M.Romanic
(2002).
Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase.
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Acta Crystallogr D Biol Crystallogr, 58,
1182-1192.
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PDB code:
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M.W.Olson,
M.M.Bernardo,
M.Pietila,
D.C.Gervasi,
M.Toth,
L.P.Kotra,
I.Massova,
S.Mobashery,
and
R.Fridman
(2000).
Characterization of the monomeric and dimeric forms of latent and active matrix metalloproteinase-9. Differential rates for activation by stromelysin 1.
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J Biol Chem, 275,
2661-2668.
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D.E.Brodersen,
J.Nyborg,
and
M.Kjeldgaard
(1999).
Zinc-binding site of an S100 protein revealed. Two crystal structures of Ca2+-bound human psoriasin (S100A7) in the Zn2+-loaded and Zn2+-free states.
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Biochemistry, 38,
1695-1704.
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PDB codes:
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A.Mucha,
P.Cuniasse,
R.Kannan,
F.Beau,
A.Yiotakis,
P.Basset,
and
V.Dive
(1998).
Membrane type-1 matrix metalloprotease and stromelysin-3 cleave more efficiently synthetic substrates containing unusual amino acids in their P1' positions.
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J Biol Chem, 273,
2763-2768.
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B.C.Finzel,
E.T.Baldwin,
G.L.Bryant,
G.F.Hess,
J.W.Wilks,
C.M.Trepod,
J.E.Mott,
V.P.Marshall,
G.L.Petzold,
R.A.Poorman,
T.J.O'Sullivan,
H.J.Schostarez,
and
M.A.Mitchell
(1998).
Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity.
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Protein Sci, 7,
2118-2126.
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PDB codes:
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G.Keyszer,
A.Redlich,
T.Häupl,
J.Zacher,
M.Sparmann,
U.Engethüm,
S.Gay,
and
G.R.Burmester
(1998).
Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: a parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry.
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Arthritis Rheum, 41,
1378-1387.
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J.S.Mudgett,
N.I.Hutchinson,
N.A.Chartrain,
A.J.Forsyth,
J.McDonnell,
I.I.Singer,
E.K.Bayne,
J.Flanagan,
D.Kawka,
C.F.Shen,
K.Stevens,
H.Chen,
M.Trumbauer,
and
D.M.Visco
(1998).
Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction.
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Arthritis Rheum, 41,
110-121.
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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
