PDBsum entry 1hv5

Hydrolase

PDB id: 1hv5

Contents

Protein chains

(+ 0 more) 162 a.a. *

Ligands

CPS ×12

RXP ×6

Metals

_ZN ×12

_CA ×6

Waters ×2136

* Residue conservation analysis

PDB id:

1hv5

Name:

Hydrolase

Title:

Crystal structure of the stromelysin-3 (mmp-11) catalytic domain complexed with a phosphinic inhibitor

Structure:

Stromelysin 3. Chain: a, b, c, d, e, f. Synonym: matrix metalloproteinase 11, mmp-11, st3, sl-3. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: stro3 (101-264). Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Biol. unit:

Dimer (from PQS)

Resolution:

2.60Å R-factor: 0.218 R-free: 0.262

Authors:

A.L.Gall,M.Ruff,R.Kannan,P.Cuniasse,A.Yiotakis,V.Dive,M.C.Rio, P.Basset,D.Moras

Key ref:

A.L.Gall et al. (2001). Crystal structure of the stromelysin-3 (MMP-11) catalytic domain complexed with a phosphinic inhibitor mimicking the transition-state. J Mol Biol, 307, 577-586. PubMed id: 11254383 DOI: 10.1006/jmbi.2001.4493

Date:

08-Jan-01 Release date: 28-Mar-01

Protein chains

Q02853  (MMP11_MOUSE) -  Stromelysin-3 from Mus musculus

Seq: 492 a.a.

Struc: 162 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.4.24.- - ?????

DOI no: 10.1006/jmbi.2001.4493

J Mol Biol 307:577-586 (2001)

PubMed id: 11254383

Crystal structure of the stromelysin-3 (MMP-11) catalytic domain complexed with a phosphinic inhibitor mimicking the transition-state.

A.L.Gall, M.Ruff, R.Kannan, P.Cuniasse, A.Yiotakis, V.Dive, M.C.Rio, P.Basset, D.Moras.

ABSTRACT

Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP-11) whose proteolytic activity plays an important role in tumorigenicity enhancement. In breast cancer, ST3 is a bad prognosis marker: its expression is associated with a poor clinical outcome. This enzyme therefore represents an attractive therapeutic target.The topology of matrix metalloproteinases (MMPs) is remarkably well conserved, making the design of highly specific inhibitors difficult. The major difference between MMPs lies in the S(1)' subsite, a well-defined hydrophobic pocket of variable depth. The present crystal structure, the first 3D-structure of the ST3 catalytic domain in interaction with a phosphinic inhibitor mimicking a (d, l) peptide, clearly demonstrates that its S(1)' pocket corresponds to a tunnel running through the enzyme. This open channel is filled by the inhibitor P(1)' group which adopts a constrained conformation to fit this pocket, together with two water molecules interacting with the ST3-specific residue Gln215. These observations provide clues for the design of more specific inhibitors and show how ST3 can accommodate a phosphinic inhibitor mimicking a (d, l) peptide.The presence of a water molecule interacting with one oxygen atom of the inhibitor phosphinyl group and the proline residue of the Met-turn suggests how the intermediate formed during proteolysis may be stabilized. Furthermore, the hydrogen bond distance observed between the methyl of the phosphinic group and the carbonyl group of Ala182 mimics the interaction between this carbonyl group and the amide group of the cleaved peptidic bond. Our crystal structure provides a good model to study the MMPs mechanism of proteolysis.

Selected figure(s)

Figure 1.
Figure 1. Crystal structure of the stromelysin-3 catalytic domain complexed with the phosphinic inhibitor. (a) Ribbon diagram showing the catalytic domain of ST3 (blue), the phosphinic inhibitor (pink), the two zinc atoms (red spheres) and the calcium atom (blue sphere). The Figure was created with Setor.[45] (b) The molecular surface of the ST3 catalytic domain is coloured according to its potential (red: negatively charged residues; blue, positively charged residues). The catalytic zinc atom (green) lies on the surface of the active site. The Figure was created with GRASP. [46]

Figure 4.
Figure 4. Inhibitor binding mode. (a) The molecular surface of the ST3 active site. The catalytic zinc atom (green) lies on the surface. The figure was created with GRASP.[46] (b) The S[1]' pocket is a deep cavity filled by the P[1]' group of the phosphinic inhibitor RXP03 and two water molecules (blue spheres). The ST3 surface (in yellow) is coloured in green at the position of Gln215. The Figure was created with DINO (DINO: Visualizing Structural Biology developped by Ansgar Philippsen; http://www.bioz.unibas.ch/ not, vert, similar-xray/dino). (c) Final 2F[obs] -F[calc] electron density map (white) in the ST3 active site, contoured at 1.0 sigma. Two of the three His side-chains ligating the catalytic zinc atom (red sphere) are represented. The phosphinic inhibitor is coloured in pink. The Figure was created with Setor.[45]

The above figures are reprinted by permission from Elsevier: J Mol Biol (2001, 307, 577-586) copyright 2001.

Figures were selected by the author.