Dr. Kirill Nadezhdin
NIH CryoEM Webinars 2023

Structural Mechanisms of TRPM7 Activation and Inhibition Revealed by Cryo-EM

Dr. Kirill Nadezhdin, Columbia University


Transient receptor potential (TRP) channels are polymodal molecular sensors involved in numerous physiological processes and implicated in various human diseases. Among the melastatin subfamily of TRP channels, TRPM7 stands out as a master regulator of the organismal balance of divalent cations, and it is linked to neuronal and cardiovascular disorders, tumor progression, and also emerged as a new drug target. By utilizing cryo-EM, functional analysis, and molecular dynamics simulations, we have uncovered two distinct structural mechanisms of TRPM7 activation: one driven by a gain-of-function mutation and the other by the agonist naltriben. These mechanisms exhibit different conformational dynamics and domain involvement. Additionally, we have identified a binding site for highly potent and selective inhibitors, demonstrating that they function by stabilizing the closed state of TRPM7. These discovered structural mechanisms lay the foundation for understanding the molecular basis of TRPM7 channelopathies and for drug development.

About Dr. Kirill Nadezhdin

Postdoctoral Research Scientist, Sobolevsky Lab, Department of Biochemistry and Molecular Biophysics

Audience: Public