Screening of Matrix Metalloproteinases Available from the Protein Data Bank:  Insights into Biological Functions, Domain Organization, and Zinc Binding Groups

Abstract

A total of 142 matrix metalloproteinase (MMP) X-ray crystallographic structures were retrieved from the Protein Data Bank (PDB) and analyzed by an automated and efficient routine, developed in-house, with a series of bioinformatic tools. Highly informative heat maps and hierarchical clusterograms provided a reliable and comprehensive representation of the relationships existing among MMPs, enlarging and complementing the current knowledge in the field. Multiple sequence and structural alignments permitted better location and display of key MMP motifs and quantification of the residue consensus at each amino acid position in the most critical binding subsites of MMPs. The MMP active site consensus sequences, the C-alpha root-mean-square deviation (RMSd) analysis of diverse enzymatic subsites, and the examination of the chemical nature, binding topologies, and zinc binding groups (ZBGs) of ligands extracted from crystallographic complexes provided useful insights on the structural arrangements of the most potent MMP inhibitors.

A combined molecular modeling study on gelatinases and their potent inhibitors

“…3), it gave the similarity and identity of 66% and 86%, respectively, indicating the high similarity between two proteins. There are six important 55 which appears to be the primary site for achieving selective interactions. 33 This pocket have the interaction with the hydrophobic group P 0 1 of ligand (see Fig.…”

“…Nicolotti et al 55 employed 142 MMP X-ray crystallographic structures retrieved from Protein Data Bank (PDB) using multiple sequence and structure alignment to analyze most critical binding subsites of MMPs and ZBGs in detail. Their work was mainly from the view of proteins.…”

Pharmacomodulation of Broad Spectrum Matrix Metalloproteinase Inhibitors Towards Regulation of Gelatinases

“…The conserved amino acid residues in gelatinases active-site region (Cuniasse et al, 2005;Kontogiorgis et al, 2005;Nicolotti et al, 2007;Rao, 2005) are given in Table 2.…”

“…Its shape is www.intechopen.com Table 2. Overview of favorable ligand properties and conserved domains of gelatinases (adapted from Cuniasse et al, 2005;Nicolotti et al, 2007;Terp et al, 2002). dependent on the amino acid residue Pro at the position 87, then the MMP-2 has its Phe87 leading to a small and hydrophobic pocket and MMP-2 interacts with positive charge probes.…”

A novel matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and targets ERK1/2 phosphorylation

“…In these compounds as well as in other MMPIs the hydroxamic acid moiety is used as well-accepted Zn 2þ binding group 19,20 . Great attention has been paid to the appropriate hydrophobic interactions between the lipophilic groups of the inhibitor and S1'pocket of MMPs 21,22 . The latter approach has led to selective MMPIs that do not require interaction with the catalytic Zn 2þ cation 23,24 .…”