PDBsum entry 2tmp

Metalloprotease inhibitor

PDB id: 2tmp

Contents

Protein chain

127 a.a. *

* Residue conservation analysis

PDB id:

2tmp

Name:

Metalloprotease inhibitor

Title:

N-terminal domain of tissue inhibitor of metalloproteinase-2 (n-timp- 2), nmr, 49 structures

Structure:

Tissue inhibitor of metalloproteinases-2. Chain: a. Fragment: n-terminal domain, residues 1-127. Synonym: metalloproteinase inhibitor, timp-2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: de3. Other_details: protein refolded from inclusion bodies

NMR struc:

49 models

Authors:

F.W.Muskett,T.A.Frenkiel,J.Feeney,R.B.Freedman,M.D.Carr, R.A.Williamson

Key ref:

F.W.Muskett et al. (1998). High resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 and characterization of its interaction site with matrix metalloproteinase-3. J Biol Chem, 273, 21736-21743. PubMed id: 9705310 DOI: 10.1074/jbc.273.34.21736

Date:

26-May-98 Release date: 09-Dec-98

Protein chain

P16035  (TIMP2_HUMAN) -  Metalloproteinase inhibitor 2 from Homo sapiens

Seq: 220 a.a.

Struc: 127 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1074/jbc.273.34.21736

J Biol Chem 273:21736-21743 (1998)

PubMed id: 9705310

High resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 and characterization of its interaction site with matrix metalloproteinase-3.

F.W.Muskett, T.A.Frenkiel, J.Feeney, R.B.Freedman, M.D.Carr, R.A.Williamson.

ABSTRACT

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.

Selected figure(s)

Figure 3.
Fig. 3. Ramachandran plot of the 49 converged structures of N-TIMP 2. All residues are shown except Pro and Gly.

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).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (1998, 273, 21736-21743) copyright 1998.

Figures were selected by an automated process.