Structural mechanisms of TRPM7 activation and inhibition
Published on 05.08.2023 in Nature Communications
Kirill D. Nadezhdin, Leonor Correia, Chamali Narangoda, Dhilon S. Patel, Arthur Neuberger, Thomas Gudermann, Maria G. Kurnikova, Vladimir Chubanov and Alexander I. Sobolevsky
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.
Structural rearrangements in TRPM7 caused by the N1098 mutation or binding of the agonist naltriben:
Permeation of Na+ ions through the TRPM7-N1098Qopen channel in the absence of applied voltage. Two Na+ ions permeating the lower gate are shown as orange and purple spheres. Non-permeating Na+ ions are shown as grey spheres. The simulation was started with no ions in the pore and a Na+ ion (shown in orange) placed below the gate entrance. The protein is shown in yellow ribbon representation. Only the pore forming regions of two protein subunits are shown, with the front and back subunits omitted for clarity. Pore lining residues F1045, G1046, E1047, Y1085, I1093, and N1097 are shown as sticks. Water molecules are shown as transparent red and white balls and sticks. Lipids are shown as white sticks. The length of the shown trajectory is 4.8 ns:
Great collaboration with Vladimir Chubanov group from Ludwig-Maximilians-University of Munich and Maria Kurnikova group from Carnegie Mellon University.
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