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

Authors

  • Deep Sankar Rudra,

    1. Drug Development Diagnostics and Biotechnology Division, Department of Physiology, Indian Institute of Chemical Biology, Kolkata, India
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    • Both the authors contributed equally and should be considered joint co-first authors.
  • Uttam Pal,

    1. Department of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Kolkata, India
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    • Both the authors contributed equally and should be considered joint co-first authors.
  • Nakul Chandra Maiti,

    1. Department of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Kolkata, India
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  • Russel J. Reiter,

    1. Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
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  • Snehasikta Swarnakar

    Corresponding author
    • Drug Development Diagnostics and Biotechnology Division, Department of Physiology, Indian Institute of Chemical Biology, Kolkata, India
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Address reprint requests to Snehasikta Swarnakar, Department of Physiology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata – 700 032, India.

E-mail: snehasiktas@hotmail.com

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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