Structural mechanisms of TRPM7 activation and inhibition

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. Authors present the structural mechanisms of TRPM7 spontaneous and agonist-induced opening and inhibition by potent and selective antagonists.

Automated summary

The transient receptor potential channel TRPM7 is a crucial regulator of divalent cation balance in the body, impacting various biological processes such as embryonic development, immune responses, and cell functionalities. It is linked to neuronal and cardiovascular disorders as well as tumor progression, highlighting its potential as a drug target. Using cryo-EM, functional analysis, and molecular dynamics simulations, researchers have unraveled two distinct structural mechanisms behind TRPM7 activation through gain-of-function mutations and the agonist naltriben. These mechanisms exhibit different conformational dynamics and involve different domains. Additionally, the study identifies a binding site for potent and selective inhibitors that stabilize the closed state of TRPM7, paving the way for the development of drugs targeting TRPM7-related channelopathies.