PDBsum entry 1a85

Hydrolase/hydrolase inhibitor

PDB id: 1a85

Contents

Protein chain

158 a.a. *

Ligands

0DY

Metals

_CA ×2

_ZN ×2

* Residue conservation analysis

PDB id:

1a85

Name:

Hydrolase/hydrolase inhibitor

Title:

Mmp8 with malonic and asparagine based inhibitor

Structure:

Mmp-8. Chain: a. Synonym: matrix metalloproteinase-8. Ec: 3.4.24.34

Source:

Homo sapiens. Human. Organism_taxid: 9606

Resolution:

2.00Å R-factor: not given

Authors:

H.Brandstetter,E.G.V.Roedern,F.Grams,R.A.Engh

Key ref:

H.Brandstetter et al. (1998). Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data. Protein Sci, 7, 1303-1309. PubMed id: 9655333 DOI: 10.1002/pro.5560070605

Date:

03-Apr-98 Release date: 27-Apr-99

Protein chain

P22894  (MMP8_HUMAN) -  Neutrophil collagenase from Homo sapiens

Seq: 467 a.a.

Struc: 158 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: Ca(2+); Zn(2+)

DOI no: 10.1002/pro.5560070605

Protein Sci 7:1303-1309 (1998)

PubMed id: 9655333

Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.

H.Brandstetter, R.A.Engh, E.G.Von Roedern, L.Moroder, R.Huber, W.Bode, F.Grams.

ABSTRACT

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.

Selected figure(s)

Figure 2.
Fig. 2. The 2f0 - fc eletrondensity for inhibitor HONE-iBM-L-Asn-NHBn(m-NH2) atthezincbinding site. Thedensity confirms bindingofthe S-S stereoisomer. Disorder oftheisobutyl group isindicated by thebranchinofthedensityat Cp. ed spheres ndicae watermolecules:anetwork of waterisinvolved in binding.

Figure 4.
Fig. 4. Schematic summaryofbinding interactions for HONH-iBM-L-Asp-NHBn,and HONH-~BM-L-A~~-NHBN(~-NH~). CH-0 type are listedinparentheses.lthough the ovrallsetof interactions emain similar, specific interactions change with the eta-aino group of HONH-iBM-L-Asn-NHBn(m-NH2) (hydrogen bond to Leu193CO).theAsp-Asnrepacement (likely interposi- ionofawater molecule), anda shift n the inhibitor position (weaker interactions toawater molecule).

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1998, 7, 1303-1309) copyright 1998.

Figures were selected by an automated process.