Exploration of the zinc finger motif in controlling activity of matrix metalloproteinases.
Discovering ways to control the activity of matrix metalloproteinases (MMPs), zinc-dependent enzymes capable of degrading extracellular matrix proteins, is an important field of cancer research. We report here a novel strategy for assembling MMP inhibitors on the basis of oligopeptide ligands by exploring the pattern known as the zinc finger motif. Advanced molecular modeling tools were used to characterize the structural binding motifs of experimentally tested MMP inhibitors, as well as those of newly proposed peptidomimetics, in their zinc-containing active sites. The results of simulations based on the quantum mechanics/molecular mechanics (QM/MM) approach and Car-Parrinello molecular dynamics with QM/MM potentials demonstrate that, upon binding of Regasepin1, a known MMP-9 inhibitor, the Zn(2+)(His3) structural element is rearranged to the Zn(2+)(Cys2His2) zinc finger motif, in which two Cys residues are borrowed from the ligand. Following consideration of the crystal structure of MMP-2 with its inhibitor, the oligopeptide APP-IP, we proposed a new peptidomimetic with two replacements in the substrate, Tyr3Cys and Asp6Cys. Simulations show that this peptide variant blocks an enzyme active site by the Zn(2+)(Cys2His2) zinc finger construct. Similarly, a natural substrate of MMP-2, Ace-Gln-Gly ∼ Ile-Ala-Gly-Nme, can be converted to an inhibiting compound by two replacements, Ile by Cys and Gly by the d isomer of Cys, favoring formation of the zinc finger motif.
A.N. Bach Institute of Biochemistry of the Russian Academy of Science, Leninsky Prospect, 33, Moscow 119071, Russian Federation.
Maria G
MG
Khrenova
Alexander P
AP
Savitsky
Igor A
IA
Topol
Alexander V
AV
Nemukhin
D003198:Computer Simulation; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D011789:Quantum Theory; D016335:Zinc Fingers
D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; C503826:Regasepin1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9