Uttam Pal - Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site

Document created by Uttam Pal on Dec 25, 2015
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  Publication Details (including relevant citation   information):

  Rudra, Deep Sankar, Pal, Uttam, Maiti, Nakul Chandra, Reiter,   Russel J, Swarnakar, Snehasikta -

  Abstract: The zinc-dependent matrix   metalloproteinases (MMPs) are key enzymes associated with   extracellular matrix (ECM) remodeling; they play critical roles   under both physiological and pathological conditions. MMP-9   activity is linked to many pathological processes, including   rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor   growth, and cancer metastasis. Specific inhibition of MMP-9   activity may be a promising target for therapy for diseases   characterized by dysregulated ECM turnover. Potent MMP-9   inhibitors including an indole scaffold were recently reported in   an X-ray crystallographic study. Herein, we addressed whether   melatonin, a secretory product of pineal gland, has an inhibitory   effect on MMP-9 function. Gelatin zymographic analysis showed a   significant reduction in pro- and active MMP-9 activity in vitro   in a dose- and time-dependent manner. In addition, a human   gastric adenocarcinoma cell line (AGS) exhibited a reduced (~50%)   MMP-9 expression when incubated with melatonin, supporting an   inhibitory effect of melatonin on MMP-9. Atomic-level interaction   between melatonin and MMP-9 was probed with computational   chemistry tools. Melatonin docked into the active site cleft of   MMP-9 and interacted with key catalytic site residues including   the three histidines that form the coordination complex with the   catalytic zinc as well as proline 421 and alanine 191. We   hypothesize that under physiological conditions, tight binding of   melatonin in the active site might be involved in reducing the   catalytic activity of MMP-9. This finding could provide a novel   approach to physical docking of biomolecules to the catalytic   site of MMPs, which inhibits this protease, to arrest   MMP-9-mediated inflammatory signals.

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