1a86
From Proteopedia
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MMP8 WITH MALONIC AND ASPARTIC ACID BASED INHIBITOR
Overview
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.
About this Structure
1A86 is a Single protein structure of sequence from Homo sapiens with CA and ZN as ligands. Active as Neutrophil collagenase, with EC number 3.4.24.34 Full crystallographic information is available from OCA.
Reference
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data., Brandstetter H, Engh RA, Von Roedern EG, Moroder L, Huber R, Bode W, Grams F, Protein Sci. 1998 Jun;7(6):1303-9. PMID:9655333
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