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Structural mechanisms of TRPM7 activation and inhibition

Kirill D. NadezhdinDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USALeonor CorreiaWalther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, GermanyChamali NarangodaChemistry Department, Carnegie Mellon University, Pittsburgh, PA, USADhilon S. PatelChemistry Department, Carnegie Mellon University, Pittsburgh, PA, USAArthur NeubergerDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USAThomas GudermannComprehensive Pneumology Center, German Center for Lung Research (DZL), Munich, GermanyMaria G. KurnikovaChemistry Department, Carnegie Mellon University, Pittsburgh, PA, USA. [email protected]Vladimir ChubanovWalther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany. [email protected]Alexander I. SobolevskyDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. [email protected]

2023en

ABI

Annotatsiya

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.

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DOI: 10.1038/s41467-023-38362-3

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