PDBsum entry: 1bzs

Hydrolase

PDB id: 1bzs

Contents

Protein chain

165 a.a. *

Ligands

BSI

EPE

Metals

_CA ×2

_ZN ×2

Waters ×208

* Residue conservation analysis

PDB id:

1bzs

Name:

Hydrolase

Title:

Crystal structure of mmp8 complexed with hmr2909

Structure:

Neutrophil collagenase. Chain: a. Fragment: catalytic domain. Synonym: mmp-8. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell: neutrophil. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Expression_system_variant: bl21.

Resolution:

1.70Å R-factor: 0.192

Authors:

H.Schreuder,V.Brachvogel,P.Loenze

Key ref:

H.Matter et al. (1999). Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis. J Med Chem, 42, 1908-1920. PubMed id: 10354399 DOI: 10.1021/jm980631s

Date:

04-Nov-98 Release date: 31-May-00

Protein chain

P22894  (MMP8_HUMAN) -  Neutrophil collagenase

Seq: 467 a.a.

Struc: 165 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.4.24.34 - Neutrophil collagenase.
• Reaction: Cleavage of interstitial collagens in the triple helical domain. Unlike EC 3.4.24.7, this enzyme cleaves type III collagen more slowly than type I.
• Cofactor: Calcium; Zinc

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular matrix (1 term)
• Biological process: proteolysis (1 term)
• Biochemical function: metallopeptidase activity (3 terms)

DOI no: 10.1021/jm980631s

J Med Chem 42:1908-1920 (1999)

PubMed id: 10354399

Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis.

H.Matter, W.Schwab, D.Barbier, G.Billen, B.Haase, B.Neises, M.Schudok, W.Thorwart, H.Schreuder, V.Brachvogel, P.Lönze, K.U.Weithmann.

ABSTRACT

A set of 90 novel 2-(arylsulfonyl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) was designed, synthesized, and investigated by 3D-QSAR techniques (CoMFA, CoMSIA) and X-ray structure analysis. Docking studies of a reference compound are based on crystal structures of MMP-8 complexed with peptidic inhibitors to propose a model of its bioactive conformation. This model was validated by a 1. 7 A X-ray structure of the catalytic domain of MMP-8. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r2 values using the leave-one-out method, repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined MMP-8 catalytic site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. This allowed to compensate the weaker zinc binding properties of carboxylates by introducing optimal fitting P1' residues. The final QSAR information agrees with all experimental data for the binding topology and thus provides clear guidelines and accurate activity predictions for novel MMP-8 inhibitors.