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PDBsum entry 2tmp
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Metalloprotease inhibitor
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PDB id
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2tmp
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References listed in PDB file
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Key reference
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Title
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High resolution structure of the n-Terminal domain of tissue inhibitor of metalloproteinases-2 and characterization of its interaction site with matrix metalloproteinase-3.
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Authors
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F.W.Muskett,
T.A.Frenkiel,
J.Feeney,
R.B.Freedman,
M.D.Carr,
R.A.Williamson.
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Ref.
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J Biol Chem, 1998,
273,
21736-21743.
[DOI no: ]
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PubMed id
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Abstract
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The high resolution structure of the N-terminal domain of tissue inhibitor of
metalloproteinases-2 (N-TIMP-2) in solution has been determined using
multidimensional heteronuclear NMR spectroscopy, with the structural
calculations based on an extensive set of constraints, including 3132 nuclear
Overhauser effect-based distance constraints, 56 hydrogen bond constraints, and
220 torsion angle constraints (an average of 26.9 constraints/residue). The core
of the protein consists of a five-stranded beta-barrel that is homologous to the
beta-barrel found in the oligosaccharide/oligonucleotide binding protein fold.
The binding site for the catalytic domain of matrix metalloproteinases-3
(N-MMP-3) on N-TIMP-2 has been mapped by determining the changes in chemical
shifts on complex formation for signals from the protein backbone (15N, 13C, and
1H). This approach identified a discrete N-MMP-3 binding site on N-TIMP-2
composed of the N terminus of the protein and the loops between beta-strands AB,
CD, and EF. The beta-hairpin formed from strands A and B in N-TIMP-2 is
significantly longer than the equivalent structure in TIMP-1, allowing it to
make more extensive binding interactions with the MMP catalytic domain. A
detailed comparison of the N-TIMP-2 structure with that of TIMP-1 bound to
N-MMP-3 (Gomis-Ruth, F.-X., Maskos, K., Betz, M., Bergner, A., Huber, R.,
Suzuki, K., Yoshida, N., Nagase, H. , Brew, K., Bourne, G. P., Bartunik, H.
& Bode, W. (1997) Nature 389, 77-80) revealed that the core beta-barrels are
very similar in topology but that the loop connecting beta-strands CD (P67-C72)
would need to undergo a large conformational change for TIMP-2 to bind in a
similar manner to TIMP-1.
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Figure 3.
Fig. 3. Ramachandran plot of the 49 converged structures
of N-TIMP 2. All residues are shown except Pro and Gly.
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Figure 6.
Fig. 6. A view of the protein backbone for N-TIMP-2
(blue) and the N-MMP-3·TIMP-1 complex (red and white)
showing the differences in structure between the bound and
unbound forms of TIMP at the TIMP/MMP interaction site. The TIMP
structures were superimposed using the coordinates of equivalent
backbone atoms in the  -barrel, and
only the N-terminal domain of TIMP-1 is shown. The two zinc ions
of the MMP-3 catalytic domain are shown in magenta (catalytic
site zinc lower left). On the right-hand side of the figure the
AB loop of TIMP-2 can clearly be seen extending far beyond the
TIMP-1 AB loop to make numerous van der Waals clashes with the
N-MMP-3 molecule. The difference in structure of the CD loops
can be seen in the center of the figure. This figure was
produced using MOLMOL (39).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(1998,
273,
21736-21743)
copyright 1998.
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Secondary reference #1
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Title
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Mapping the binding site for matrix metalloproteinase on the n-Terminal domain of the tissue inhibitor of metalloproteinases-2 by nmr chemical shift perturbation.
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Authors
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R.A.Williamson,
M.D.Carr,
T.A.Frenkiel,
J.Feeney,
R.B.Freedman.
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Ref.
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Biochemistry, 1997,
36,
13882-13889.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Chemically and conformationally authentic active domain of human tissue inhibitor of metalloproteinases-2 refolded from bacterial inclusion bodies.
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Authors
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R.A.Williamson,
D.Natalia,
C.K.Gee,
G.Murphy,
M.D.Carr,
R.B.Freedman.
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Ref.
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Eur J Biochem, 1996,
241,
476-483.
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PubMed id
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Secondary reference #3
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Title
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Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the ob fold protein family.
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Authors
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R.A.Williamson,
G.Martorell,
M.D.Carr,
G.Murphy,
A.J.Docherty,
R.B.Freedman,
J.Feeney.
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Ref.
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Biochemistry, 1994,
33,
11745-11759.
[DOI no: ]
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PubMed id
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Secondary reference #4
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Title
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Disulphide bond assignment in human tissue inhibitor of metalloproteinases (timp).
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Authors
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R.A.Williamson,
F.A.Marston,
S.Angal,
P.Koklitis,
M.Panico,
H.R.Morris,
A.F.Carne,
B.J.Smith,
T.J.Harris,
R.B.Freedman.
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Ref.
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Biochem J, 1990,
268,
267-274.
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PubMed id
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