PDBsum entry 1m1v

Hydrolase

PDB id: 1m1v

Contents

Protein chain

197 a.a.

Ligands

ALA-ALA-LEU-TYR-LEU-VAL-CYS-GLY

Metals

_ZN

Theoretical model

PDB id:

1m1v

Name:

Hydrolase

Title:

Exploring the substrate affinities of mmp-3, adam-9 and adam-10 using molecular modelling and dynamics simulations

Structure:

Meltrin gamma. Chain: a. Fragment: catalytic domain. Synonym: a disintegrin and metalloproteinase domain 9. Metalloprotease/disintegrin/cysteine-rich protein. Adam-9. Empirical substrate. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Synthetic: yes

Ensemble:

2 models

Authors:

S.Manzetti,D.R.Mcculloch,A.C.Herington

Key ref:

S.Manzetti et al. (2003). Modeling of enzyme-substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10. J Comput Aided Mol Des, 17, 551-565. PubMed id: 14713188

Date:

20-Jun-02 Release date: 05-Jul-02

Supersedes:

1knh

Protein chain

No UniProt id for this chain

Struc: 197 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.24.17 - stromelysin 1.
• Reaction: Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
• Cofactor: Ca(2+); Zn(2+)

J Comput Aided Mol Des 17:551-565 (2003)

PubMed id: 14713188

Modeling of enzyme-substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10.

S.Manzetti, D.R.McCulloch, A.C.Herington, D.van der Spoel.

ABSTRACT

The matrix metalloproteases (MMPs) and the ADAMs (A Disintegrin And Metalloprotease domain) are proteolytic enzyme families containing a catalytic zinc ion, that are implicated in a variety of normal and pathological processes involving tissue remodeling and cancer. Synthetic MMP inhibitors have been designed for applications in pathological situations. However, a greater understanding of substrate binding and the catalytic mechanism is required so that more effective and selective inhibitors may be developed for both experimental and clinical purposes. By modeling a natural substrate spanning P4-P4' in complex with the catalytic domains, we aim to compare substrate-specificities between Stromelysin-1 (MMP-3), ADAM-9 and ADAM-10, with the aid of molecular dynamics simulations. Our results show that the substrate retains a favourable antiparallel beta-sheet conformation on the P-side in addition to the well-known orientation of the P'-region of the scissile bond, and that the primary substrate selectivity is dominated by the sidechains in the S1' pocket and the S2/S3 region. ADAM-9 has a hydrophobic residue as the central determinant in the S1' pocket, while ADAM-10 has an amphiphilic residue, which suggests a different primary specificity. The S2/S3 pocket is largely hydrophobic in all three enzymes. Inspired by our molecular dynamics calculations and supported by a large body of literature, we propose a novel, hypothetical, catalytic mechanism where the Zn-ion polarizes the oxygens from the catalytic glutamate to form a nucleophile, leading to a tetrahedral oxyanion anhydride transition state.