Abstract
Malignant tumors express high levels of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs), which are thought to facilitate tumor metastasis and angiogenesis by hydrolyzing components of the extracellular matrix. Of these enzymes, gelatinases A (MMP-2) and B (MMP-9), have especially been implicated in malignant processes, and thus, they have been a target for drugs designed to block their activity. Therefore, understanding their molecular structure is key for a rational approach to inhibitor design. Here, we have conducted x-ray absorption spectroscopy of the full-length human MMP-2 in its latent, active, and inhibited states and report the structural changes at the zinc ion site upon enzyme activation and inhibition. We have also examined the molecular structure of MMP-2 in complex with SB-3CT, a recently reported novel mechanism-based synthetic inhibitor that was designed to be highly selective in gelatinases. It is shown that SB-3CT directly binds the catalytic zinc ion of MMP-2. Interestingly, the novel mode of binding of the inhibitor to the catalytic zinc reconstructs the conformational environment around the active site metal ion back to that of the proenzyme.
Highlights
Malignant tumors express high levels of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs), which are thought to facilitate tumor metastasis and angiogenesis by hydrolyzing components of the extracellular matrix
We have examined the molecular structure of MMP-2 in complex with SB-3CT, a recently reported novel mechanismbased synthetic inhibitor that was designed to be highly selective in gelatinases [1]
In this work we present the local structure of the catalytic site zinc ions in MMP-2
Summary
Malignant tumors express high levels of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs), which are thought to facilitate tumor metastasis and angiogenesis by hydrolyzing components of the extracellular matrix Of these enzymes, gelatinases A (MMP-2) and B (MMP-9), have especially been implicated in malignant processes, and they have been a target for drugs designed to block their activity. We have examined the molecular structure of MMP-2 in complex with SB-3CT, a recently reported novel mechanismbased synthetic inhibitor that was designed to be highly selective in gelatinases [1]. To gain insight into the mechanism of inhibition of MMP-2 by SB-3CT and the local structure around the catalytic zinc ion in latent, active, and inhibited MMP-2, the zinc ion coordination shell in all complexes was studied by x-ray absorption spectroscopy (XAS). The inhibited enzyme retains the conformation of the latent MMP-2 around the zinc coordination shell, which may explain the remarkable selectivity of SB-3CT for gelatinases for which it was designed
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