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PDBsum entry 2tcl
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Hydrolase (metalloprotease)
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PDB id
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2tcl
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.24.7
- interstitial collagenase.
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Reaction:
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Cleaves preferentially one bond in native collagen. Cleavage of the triple helix of collagen at about three-quarters of the length of the molecule from the N-terminus, at 775-Gly-|-Ile-776 in the alpha-1(I) chain. Cleaves synthetic substrates and alpha-macroglobulins at bonds where P1' is a hydrophobic residue.
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Cofactor:
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Zn(2+)
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Nat Struct Biol
1:106-110
(1994)
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PubMed id:
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Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibitor.
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N.Borkakoti,
F.K.Winkler,
D.H.Williams,
A.D'Arcy,
M.J.Broadhurst,
P.A.Brown,
W.H.Johnson,
E.J.Murray.
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ABSTRACT
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In rheumatoid and osteoarthritis, degradation of articular cartilage is mediated
by the matrix metalloproteinases collagenase, stromelysin and gelatinase. The
key event in this process is the cleavage of triple helical collagen by
collagenase. We have determined the crystal structure of the catalytic domain of
human recombinant fibroblast collagenase complexed with a synthetic inhibitor at
2.2 A resolution. The protein fold is similar to the amino termini of the zinc
endopeptidases astacin thermolysin and elastase despite a lack of primary
sequence homology. The conformation of the bound inhibitor provides a molecular
basis for the design of inhibitors of collagenase and other matrix
metalloproteinases. Such inhibitors should be useful in the treatment of a
variety of diseases including arthritis and cancer.
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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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N.P.Todorov,
C.L.Buenemann,
and
I.L.Alberts
(2006).
De novo ligand design to an ensemble of protein structures.
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Proteins,
64,
43-59.
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Y.Itoh,
N.Ito,
H.Nagase,
R.D.Evans,
S.A.Bird,
and
M.Seiki
(2006).
Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMP.
|
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Mol Biol Cell,
17,
5390-5399.
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M.B.Onaran,
A.B.Comeau,
and
C.T.Seto
(2005).
Squaric acid-based peptidic inhibitors of matrix metalloprotease-1.
|
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J Org Chem,
70,
10792-10802.
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P.L.Tsai,
C.H.Chen,
C.J.Huang,
C.M.Chou,
and
G.D.Chang
(2004).
Purification and cloning of an endogenous protein inhibitor of carp nephrosin, an astacin metalloproteinase.
|
| |
J Biol Chem,
279,
11146-11155.
|
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S.Ravaud,
P.Gouet,
R.Haser,
and
N.Aghajari
(2003).
Probing the role of divalent metal ions in a bacterial psychrophilic metalloprotease: binding studies of an enzyme in the crystalline state by x-ray crystallography.
|
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J Bacteriol,
185,
4195-4203.
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PDB codes:
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V.J.Uitto,
C.M.Overall,
and
C.McCulloch
(2003).
Proteolytic host cell enzymes in gingival crevice fluid.
|
| |
Periodontol 2000,
31,
77.
|
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W.Bode,
and
K.Maskos
(2003).
Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.
|
| |
Biol Chem,
384,
863-872.
|
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J.L.Lauer-Fields,
and
G.B.Fields
(2002).
Triple-helical peptide analysis of collagenolytic protease activity.
|
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Biol Chem,
383,
1095-1105.
|
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K.Kaur,
K.Zhu,
M.S.Whittemore,
R.L.Petersen,
A.Lichte,
H.Tschesche,
and
T.Pourmotabbed
(2002).
Identification of the active site of gelatinase B as the structural element sufficient for converting a protein to a metalloprotease.
|
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Biochemistry,
41,
4789-4797.
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M.Gioia,
G.F.Fasciglione,
S.Marini,
S.D'Alessio,
G.De Sanctis,
O.Diekmann,
M.Pieper,
V.Politi,
H.Tschesche,
and
M.Coletta
(2002).
Modulation of the catalytic activity of neutrophil collagenase MMP-8 on bovine collagen I. Role of the activation cleavage and of the hemopexin-like domain.
|
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J Biol Chem,
277,
23123-23130.
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F.Grams,
H.Brandstetter,
S.D'Alò,
D.Geppert,
H.W.Krell,
H.Leinert,
V.Livi,
E.Menta,
A.Oliva,
G.Zimmermann,
F.Gram,
H.Brandstetter,
S.D'Alò,
D.Geppert,
H.W.Krell,
H.Leinert,
E.Livi VMenta,
A.Oliva,
and
G.Zimmermann
(2001).
Pyrimidine-2,4,6-Triones: a new effective and selective class of matrix metalloproteinase inhibitors.
|
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Biol Chem,
382,
1277-1285.
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V.Knäuper,
M.L.Patterson,
F.X.Gomis-Rüth,
B.Smith,
A.Lyons,
A.J.Docherty,
and
G.Murphy
(2001).
The role of exon 5 in fibroblast collagenase (MMP-1) substrate specificity and inhibitor selectivity.
|
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Eur J Biochem,
268,
1888-1896.
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J.L.Lauer-Fields,
K.A.Tuzinski,
K.Shimokawa,
H.Nagase,
and
G.B.Fields
(2000).
Hydrolysis of triple-helical collagen peptide models by matrix metalloproteinases.
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J Biol Chem,
275,
13282-13290.
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J.Ottl,
D.Gabriel,
G.Murphy,
V.Knäuper,
Y.Tominaga,
H.Nagase,
M.Kröger,
H.Tschesche,
W.Bode,
and
L.Moroder
(2000).
Recognition and catabolism of synthetic heterotrimeric collagen peptides by matrix metalloproteinases.
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Chem Biol,
7,
119-132.
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A.G.Pavlovsky,
M.G.Williams,
Q.Z.Ye,
D.F.Ortwine,
C.F.Purchase,
A.D.White,
V.Dhanaraj,
B.D.Roth,
L.L.Johnson,
D.Hupe,
C.Humblet,
and
T.L.Blundell
(1999).
X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity.
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Protein Sci,
8,
1455-1462.
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PDB codes:
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C.M.Holman,
C.C.Kan,
M.R.Gehring,
and
H.E.Van Wart
(1999).
Role of His-224 in the anomalous pH dependence of human stromelysin-1.
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Biochemistry,
38,
677-681.
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G.N.Smith,
E.A.Mickler,
K.A.Hasty,
and
K.D.Brandt
(1999).
Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme.
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Arthritis Rheum,
42,
1140-1146.
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K.Briknarová,
A.Grishaev,
L.Bányai,
H.Tordai,
L.Patthy,
and
M.Llinás
(1999).
The second type II module from human matrix metalloproteinase 2: structure, function and dynamics.
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Structure,
7,
1235-1245.
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PDB code:
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L.L.Johnson,
D.A.Bornemeier,
J.A.Janowicz,
J.Chen,
A.G.Pavlovsky,
and
D.F.Ortwine
(1999).
Effect of species differences on stromelysin-1 (MMP-3) inhibitor potency. An explanation of inhibitor selectivity using homology modeling and chimeric proteins.
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J Biol Chem,
274,
24881-24887.
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T.Meinnel,
L.Patiny,
S.Ragusa,
and
S.Blanquet
(1999).
Design and synthesis of substrate analogue inhibitors of peptide deformylase.
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Biochemistry,
38,
4287-4295.
|
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W.Bode,
C.Fernandez-Catalan,
F.Grams,
F.X.Gomis-Rüth,
H.Nagase,
H.Tschesche,
and
K.Maskos
(1999).
Insights into MMP-TIMP interactions.
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Ann N Y Acad Sci,
878,
73-91.
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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.
|
| |
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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B.J.Stockman,
D.J.Waldon,
J.A.Gates,
T.A.Scahill,
D.A.Kloosterman,
S.A.Mizsak,
E.J.Jacobsen,
K.L.Belonga,
M.A.Mitchell,
B.Mao,
J.D.Petke,
L.Goodman,
E.A.Powers,
S.R.Ledbetter,
P.S.Kaytes,
G.Vogeli,
V.P.Marshall,
G.L.Petzold,
and
R.A.Poorman
(1998).
Solution structures of stromelysin complexed to thiadiazole inhibitors.
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Protein Sci,
7,
2281-2286.
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PDB code:
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F.J.Moy,
P.K.Chanda,
S.Cosmi,
M.R.Pisano,
C.Urbano,
J.Wilhelm,
and
R.Powers
(1998).
High-resolution solution structure of the inhibitor-free catalytic fragment of human fibroblast collagenase determined by multidimensional NMR.
|
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Biochemistry,
37,
1495-1504.
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PDB codes:
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H.Brandstetter,
R.A.Engh,
E.G.Von Roedern,
L.Moroder,
R.Huber,
W.Bode,
and
F.Grams
(1998).
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.
|
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Protein Sci,
7,
1303-1309.
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PDB codes:
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S.Parvathy,
I.Hussain,
E.H.Karran,
A.J.Turner,
and
N.M.Hooper
(1998).
Alzheimer's amyloid precursor protein alpha-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: similarities to the angiotensin converting enzyme secretase.
|
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Biochemistry,
37,
1680-1685.
|
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E.J.Lewis,
J.Bishop,
K.M.Bottomley,
D.Bradshaw,
M.Brewster,
M.J.Broadhurst,
P.A.Brown,
J.M.Budd,
L.Elliott,
A.K.Greenham,
W.H.Johnson,
J.S.Nixon,
F.Rose,
B.Sutton,
and
K.Wilson
(1997).
Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo.
|
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Br J Pharmacol,
121,
540-546.
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J.C.Müller,
E.G.von Roedern,
F.Grams,
H.Nagase,
and
L.Moroder
(1997).
Non-peptidic cysteine derivatives as inhibitors of matrix metalloproteinases.
|
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Biol Chem,
378,
1475-1480.
|
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M.Betz,
P.Huxley,
S.J.Davies,
Y.Mushtaq,
M.Pieper,
H.Tschesche,
W.Bode,
and
F.X.Gomis-Rüth
(1997).
1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase-8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with a distinct selectivity profile.
|
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Eur J Biochem,
247,
356-363.
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PDB code:
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B.Chevrier,
H.D'Orchymont,
C.Schalk,
C.Tarnus,
and
D.Moras
(1996).
The structure of the Aeromonas proteolytica aminopeptidase complexed with a hydroxamate inhibitor. Involvement in catalysis of Glu151 and two zinc ions of the co-catalytic unit.
|
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Eur J Biochem,
237,
393-398.
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PDB code:
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C.Tarnus,
J.M.Rémy,
and
H.d'Orchymont
(1996).
3-Amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxy-propan-2-one derivatives: new classes of aminopeptidase inhibitors.
|
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Bioorg Med Chem,
4,
1287-1297.
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D.R.Wetmore,
and
K.D.Hardman
(1996).
Roles of the propeptide and metal ions in the folding and stability of the catalytic domain of stromelysin (matrix metalloproteinase 3).
|
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Biochemistry,
35,
6549-6558.
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I.Botos,
L.Scapozza,
D.Zhang,
L.A.Liotta,
and
E.F.Meyer
(1996).
Batimastat, a potent matrix mealloproteinase inhibitor, exhibits an unexpected mode of binding.
|
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Proc Natl Acad Sci U S A,
93,
2749-2754.
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PDB code:
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R.A.Williamson,
D.Natalia,
C.K.Gee,
G.Murphy,
M.D.Carr,
and
R.B.Freedman
(1996).
Chemically and conformationally authentic active domain of human tissue inhibitor of metalloproteinases-2 refolded from bacterial inclusion bodies.
|
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Eur J Biochem,
241,
476-483.
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T.E.Cawston
(1996).
Metalloproteinase inhibitors and the prevention of connective tissue breakdown.
|
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Pharmacol Ther,
70,
163-182.
|
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V.Dhanaraj,
Q.Z.Ye,
L.L.Johnson,
D.J.Hupe,
D.F.Ortwine,
J.B.Dunbar,
J.R.Rubin,
A.Pavlovsky,
C.Humblet,
and
T.L.Blundell
(1996).
X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily.
|
| |
Structure,
4,
375-386.
|
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V.Knäuper,
C.López-Otin,
B.Smith,
G.Knight,
and
G.Murphy
(1996).
Biochemical characterization of human collagenase-3.
|
| |
J Biol Chem,
271,
1544-1550.
|
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W.D.Shingleton,
D.J.Hodges,
P.Brick,
and
T.E.Cawston
(1996).
Collagenase: a key enzyme in collagen turnover.
|
| |
Biochem Cell Biol,
74,
759-775.
|
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D.Soler,
T.Nomizu,
W.E.Brown,
Y.Shibata,
and
D.S.Auld
(1995).
Matrilysin: expression, purification, and characterization.
|
| |
J Protein Chem,
14,
511-520.
|
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|
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F.Grams,
P.Reinemer,
J.C.Powers,
T.Kleine,
M.Pieper,
H.Tschesche,
R.Huber,
and
W.Bode
(1995).
X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design.
|
| |
Eur J Biochem,
228,
830-841.
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PDB codes:
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J.W.Becker,
A.I.Marcy,
L.L.Rokosz,
M.G.Axel,
J.J.Burbaum,
P.M.Fitzgerald,
P.M.Cameron,
C.K.Esser,
W.K.Hagmann,
and
J.D.Hermes
(1995).
Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme.
|
| |
Protein Sci,
4,
1966-1976.
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PDB codes:
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S.Harada,
T.Kinoshita,
N.Kasai,
S.Tsunasawa,
and
F.Sakiyama
(1995).
Complete amino acid sequence of a zinc metalloendoprotease from Streptomyces caespitosus.
|
| |
Eur J Biochem,
233,
683-686.
|
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S.R.Van Doren,
A.V.Kurochkin,
W.Hu,
Q.Z.Ye,
L.L.Johnson,
D.J.Hupe,
and
E.R.Zuiderweg
(1995).
Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor.
|
| |
Protein Sci,
4,
2487-2498.
|
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PDB codes:
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T.Pourmotabbed,
J.A.Aelion,
D.Tyrrell,
K.A.Hasty,
C.H.Bu,
and
C.L.Mainardi
(1995).
Role of the conserved histidine and aspartic acid residues in activity and stabilization of human gelatinase B: an example of matrix metalloproteinases.
|
| |
J Protein Chem,
14,
527-535.
|
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|
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|
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W.N.Hunter
(1995).
Rational drug design: a multidisciplinary approach.
|
| |
Mol Med Today,
1,
31, 34.
|
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W.Stöcker,
F.Grams,
U.Baumann,
P.Reinemer,
F.X.Gomis-Rüth,
D.B.McKay,
and
W.Bode
(1995).
The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases.
|
| |
Protein Sci,
4,
823-840.
|
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W.Stöcker,
and
W.Bode
(1995).
Structural features of a superfamily of zinc-endopeptidases: the metzincins.
|
| |
Curr Opin Struct Biol,
5,
383-390.
|
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|
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|
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D.Zhang,
I.Botos,
F.X.Gomis-Rüth,
R.Doll,
C.Blood,
F.G.Njoroge,
J.W.Fox,
W.Bode,
and
E.F.Meyer
(1994).
Structural interaction of natural and synthetic inhibitors with the venom metalloproteinase, atrolysin C (form d).
|
| |
Proc Natl Acad Sci U S A,
91,
8447-8451.
|
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PDB codes:
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P.M.Colman
(1994).
Structure-based drug design.
|
| |
Curr Opin Struct Biol,
4,
868-874.
|
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|
|
T.L.Blundell
(1994).
Metalloproteinase superfamilies and drug design.
|
| |
Nat Struct Biol,
1,
73-75.
|
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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
