Gelatinase A

 

Matrix metalloprotease 2 (MMP 2), sourced from Homo sapiens cleaves gelatin type I and collagen types IV, V, VII and X. It specifically cleaves the collagen-like sequence Pro-Gln-Gly-|-Ile-Ala-Gly-Gln. MMP 2 belongs to a family of matrix metalloproteases (MMPs), zinc and calcium dependent enzymes responsible for the metabolism of extracellular matrix proteins. This includes normal tissue-remodelling processes such as wound healing, pregnancy and angiogenesis. Under physiological conditions, in addition to the regulated proteolysis of precursors to active form, the enzymes are also controlled by endogenous inhibitors (TIMPs).

 

Reference Protein and Structure

Sequence
P08253 UniProt (3.4.24.24) IPR028708 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1qib - CRYSTAL STRUCTURE OF GELATINASE A CATALYTIC DOMAIN (2.8 Å) PDBe PDBsum 1qib
Catalytic CATH Domains
3.40.390.10 CATHdb (see all for 1qib)
Cofactors
Zinc(2+) (1)
Click To Show Structure

Enzyme Reaction (EC:3.4.24.24)

Gly-Ile
CHEBI:73907ChEBI
+
water
CHEBI:15377ChEBI
→
glycine
CHEBI:15428ChEBI
+
isoleucine
CHEBI:24898ChEBI
Alternative enzyme names: 3/4 collagenase, 72 kDa gelatinase type A, 72-kDa gelatinase, MMP 2, Collagenase IV, Collagenase type IV, Matrix metalloproteinase 2, Matrix metalloproteinase 5, Type IV collagen metalloproteinase, Type IV collagenase, Type IV collagenase/gelatinase,

Enzyme Mechanism

Introduction

The water molecule coordinated to the zinc in the reactant centre becomes polarised between the glutamate base and the zinc Lewis acid in the Glu-H2O-Zn bridge. When the substrate binds, the polarised water molecule performs nucleophilic attack on the peptide carbon. The glutamate abstracts the proton from the water, shuttling it towards the nitrogen atom of the scissile amide. The tetrahedral intermediate formed is bidentately coordinated to the zinc atom, which stabilises it. It may also be stabilised electrostatically by an additional water molecule. The tetrahedral intermediate collapses, releasing the amine product. The carboxylate product is then released and water molecule uptake occurs.

Catalytic Residues Roles

UniProt PDB* (1qib)
His413, His403, His407 His211(125)A, His201(115)A, His205(119)A Forms part of the catalytic zinc binding site. metal ligand
Glu404 Glu202(116)A Glu 202 (UniProt number 404) acts as a general base, deprotonating the water molecule that attacks the peptide carbon. The protonated Glu 202 acts as a general acid, protonating the nitrogen atom of the scissile amide. proton shuttle (general acid/base)
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Pelmenschikov V et al. (2002), Inorg Chem, 41, 5659-5666. Catalytic Mechanism of Matrix Metalloproteinases:  Two-Layered ONIOM Study. DOI:10.1021/ic0255656. PMID:12401069.
  2. Nash A et al. (2017), J Biomol Struct Dyn, 35, 564-573. Mapping intermolecular interactions and active site conformations: from human MMP-1 crystal structure to molecular dynamics free energy calculations. DOI:10.1080/07391102.2016.1153521. PMID:26886688.
  3. Vasilevskaya T et al. (2016), J Comput Chem, 37, 1801-1809. Methodological aspects of QM/MM calculations: A case study on matrix metalloproteinase-2. DOI:10.1002/jcc.24395. PMID:27140531.
  4. Vasilevskaya T et al. (2015), J Comput Chem, 36, 1621-1630. Mechanism of proteolysis in matrix metalloproteinase-2 revealed by QM/MM modeling. DOI:10.1002/jcc.23977. PMID:26132652.
  5. Hashimoto H et al. (2011), J Biol Chem, 286, 33236-33243. Structural basis for matrix metalloproteinase-2 (MMP-2)-selective inhibitory action of β-amyloid precursor protein-derived inhibitor. DOI:10.1074/jbc.M111.264176. PMID:21813640.
  6. Borkakoti N (1998), Prog Biophys Mol Biol, 70, 73-94. Matrix metalloproteases: variations on a theme. DOI:10.1016/s0079-6107(98)00003-0. PMID:9785958.

Step 1.

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Catalytic Residues Roles

Residue Roles
Glu202(116)A proton shuttle (general acid/base)
His205(119)A metal ligand
His201(115)A metal ligand
His211(125)A metal ligand

Chemical Components

Step 1.

Contributors

Alex Gutteridge, Craig Porter, Gemma L. Holliday