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Structural mechanisms of TRPM7 activation and inhibition

Author

Listed:
  • Kirill D. Nadezhdin

    (Columbia University)

  • Leonor Correia

    (Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich)

  • Chamali Narangoda

    (Carnegie Mellon University)

  • Dhilon S. Patel

    (Carnegie Mellon University)

  • Arthur Neuberger

    (Columbia University)

  • Thomas Gudermann

    (Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich
    Comprehensive Pneumology Center, German Center for Lung Research (DZL))

  • Maria G. Kurnikova

    (Carnegie Mellon University)

  • Vladimir Chubanov

    (Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich)

  • Alexander I. Sobolevsky

    (Columbia University)

Abstract

The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. TRPM7 is implicated in neuronal and cardiovascular disorders, tumor progression and has emerged as a new drug target. Here we use cryo-EM, functional analysis, and molecular dynamics simulations to uncover two distinct structural mechanisms of TRPM7 activation by a gain-of-function mutation and by the agonist naltriben, which show different conformational dynamics and domain involvement. We identify a binding site for highly potent and selective inhibitors and show that they act by stabilizing the TRPM7 closed state. The discovered structural mechanisms provide foundations for understanding the molecular basis of TRPM7 channelopathies and drug development.

Suggested Citation

  • Kirill D. Nadezhdin & Leonor Correia & Chamali Narangoda & Dhilon S. Patel & Arthur Neuberger & Thomas Gudermann & Maria G. Kurnikova & Vladimir Chubanov & Alexander I. Sobolevsky, 2023. "Structural mechanisms of TRPM7 activation and inhibition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38362-3
    DOI: 10.1038/s41467-023-38362-3
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    References listed on IDEAS

    as
    1. Yihe Huang & Paige A. Winkler & Weinan Sun & Wei Lü & Juan Du, 2018. "Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium," Nature, Nature, vol. 562(7725), pages 145-149, October.
    2. Luke L. McGoldrick & Appu K. Singh & Kei Saotome & Maria V. Yelshanskaya & Edward C. Twomey & Robert A. Grassucci & Alexander I. Sobolevsky, 2018. "Opening of the human epithelial calcium channel TRPV6," Nature, Nature, vol. 553(7687), pages 233-237, January.
    3. Ying Yin & Mengyu Wu & Allen L. Hsu & William F. Borschel & Mario J. Borgnia & Gabriel C. Lander & Seok-Yong Lee, 2019. "Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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