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Structural mechanisms of TRPM7 activation and inhibition

Kirill D Nadezhdin1, Leonor Correia2, Chamali Narangoda3

  • 1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.

Nature Communications
|May 8, 2023
PubMed

Insights

Transient receptor potential channel TRPM7 (Transient Receptor Potential Melastatin 7) regulates cation balance and is crucial for development and disease. This study reveals TRPM7 activation mechanisms and identifies a novel inhibitor binding site.

Area of Science:

  • Biophysics
  • Molecular Biology
  • Structural Biology

Background:

  • Transient receptor potential channel TRPM7 (Transient Receptor Potential Melastatin 7) is vital for divalent cation homeostasis.
  • TRPM7 dysfunction is linked to embryonic development, immune responses, cell mobility, proliferation, differentiation, neuronal and cardiovascular disorders, and tumor progression.
  • TRPM7 is recognized as a significant drug target for various diseases.

Purpose of the Study:

  • To elucidate the structural mechanisms underlying TRPM7 activation by a gain-of-function mutation and the agonist naltriben.
  • To identify a binding site for potent and selective TRPM7 inhibitors.
  • To provide a structural basis for understanding TRPM7 channelopathies and guiding drug development.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) for high-resolution structural determination.
  • Functional assays to assess channel activity and inhibitor efficacy.
  • Molecular dynamics simulations to explore conformational dynamics.

Main Results:

  • Two distinct structural mechanisms of TRPM7 activation were uncovered, involving different conformational dynamics and domain participation.
  • A binding site for potent and selective TRPM7 inhibitors was identified.
  • Inhibitors were shown to stabilize the closed state of the TRPM7 channel.

Conclusions:

  • The study reveals novel structural insights into TRPM7 activation and inhibition.
  • Understanding these mechanisms is crucial for developing targeted therapies for TRPM7-related disorders.
  • The identified inhibitor binding site offers a promising avenue for TRPM7-targeted drug discovery.

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