PDBsum entry: 1i73

Hydrolase/hydrolase inhibitor

PDB id: 1i73

Contents

Protein chain

163 a.a. *

Ligands

PRO-LEU-PAT

Metals

_ZN ×2

_CA ×2

Waters ×281

* Residue conservation analysis

PDB id:

1i73

Name:

Hydrolase/hydrolase inhibitor

Title:

Complex of pro-leu-l-trp phosphonate with the catalitic doma matrix metallo proteinase-8 (met80 form)

Structure:

Neutrophil collagenase. Chain: a. Fragment: residues 80-242. Synonym: matrix metalloproteinase-8. Mmp-8. Engineered: yes. Three residue peptide inhibitor. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the three residue peptide inhibitor was chem synthesized

Resolution:

1.40Å R-factor: 0.138 R-free: 0.194

Authors:

E.Gavuzzo,G.Pochetti,F.Mazza,C.Gallina,B.Gorini,S.D'Alessio, H.Tschesche,P.A.Tucker

Key ref:

E.Gavuzzo et al. (2000). Two crystal structures of human neutrophil collagenase, one complexed with a primed- and the other with an unprimed-side inhibitor: implications for drug design. J Med Chem, 43, 3377-3385. PubMed id: 10978185 DOI: 10.1021/jm9909589

Date:

07-Mar-01 Release date: 21-Mar-01

Protein chain

P22894  (MMP8_HUMAN) -  Neutrophil collagenase

Seq: 467 a.a.

Struc: 163 a.a.

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/jm9909589

J Med Chem 43:3377-3385 (2000)

PubMed id: 10978185

Two crystal structures of human neutrophil collagenase, one complexed with a primed- and the other with an unprimed-side inhibitor: implications for drug design.

E.Gavuzzo, G.Pochetti, F.Mazza, C.Gallina, B.Gorini, S.D'Alessio, M.Pieper, H.Tschesche, P.A.Tucker.

ABSTRACT

Two crystal structures of human neutrophil collagenase (HNC, MMP-8), one complexed with a primed- and the other with an unprimed-side inhibitor, were determined using synchrotron radiation at 100 K. Both inhibitors contain non-hydroxamate zinc-binding functions. The Pro-Leu-L-Trp(P)(OH)(2) occupies the unprimed region of the active site, furnishes new structural information regarding interaction between the catalytic zinc ion and the phosphonate group, and is the only example of occupation of the S(1) subsite of MMP-8 by the bulky tryptophan side chain. The (R)-2-(biphenyl-4-ylsulfonyl)-1,2,3, 4-tetrahydroisochinolin-3-carboxylic acid, a conformationally constrained D-Tic derivative, accommodates its biphenyl substituent into the deep primary specificity S(1)' subsite, inducing a widening of the entrance to this pocket; this modification of the protein, mainly consisting in a shift of the segment centered at Pro217, is observed for the first time in MMP-8 complexes. Cation-aromatic interactions can stabilize the formation of both complexes, and the beneficial effect of aromatic substituents in proximity of the catalytic zinc ion is discussed. The phosphonate group bound to either a primed- or unprimed-side inhibitor maintains the same relative position with respect to the catalytic zinc ion, suggesting that this binding function can be exploited for the design of combined inhibitors assembled to interact with both primed and unprimed regions of the active cleft.