Structures of Ion Channels Help Scientists to Fight Mineral Imbalance
Published on 05.12.2023
In our recent research study published in Nature Communications, we uncovered a structural mechanism for regulating organismal levels of divalent cations through a master regulator ion channel, TRPM7.
Depression is one of the most common mental disorders in the world and the leading cause of disability in the United States for individuals ages 15-44. Depression has been linked to a Western diet that is low in essential vitamins and minerals like zinc and magnesium. Our team, which includes researchers from Columbia University, Carnegie Mellon University, and Ludwig Maximilian University of Munich, conducted a new study [link] that revealed a new understanding of how cells regulate the uptake of vital minerals magnesium, zinc, and calcium through the ion channel TRPM7.
The TRPM7, a member of melastatin family of transient receptor potential channels, plays a crucial role in regulating mineral levels within cells, which is essential for proper prenatal development, immune responses, and mental health. Recently, TRPM7 channel has been identified as a potential drug target for various diseases such as depression, neurological and cardiovascular disorders, cancers, and other conditions associated with mineral imbalances.
The study revealed two distinct structural mechanisms of TRPM7 activation: spontaneous activation and activation by a small chemical drug naltriben. Using molecular dynamics simulations conducted on supercomputer, these mechanisms were confirmed and explained what happens exactly during TRPM7 activation. Using cryogenic electron microscopy and electrophysiological methods, we also identified the specific binding site for two highly potent and selective inhibitors, VER155008 and NS8593, which can stabilize the TRPM7 ion channel’s closed state and provide new opportunities for drug development. Although these two small molecules are completely unrelated chemically, they both work similarly by stabilizing the TRPM7 ion channel’s closed state, providing new opportunities for drug development.
«Our findings provide tools for controlling the function of TRPM7 – the most critical protein for absorption of magnesium and zinc our bodies,» said Kirill Nadezhdin, postdoctoral research scientist in Sobolevsky lab and the first author of the paper, «Understanding the structural mechanisms of TRPM7 activation and inhibition is crucial for not only developing new therapeutic interventions but also for unraveling the molecular basis of several genetic diseases linked to mineral imbalance.»
Check out video cartoons about gating of TRPM7 by agonist and by a gain-of-function mutation!
1. Structural rearrangements in TRPM7 caused by the N1098 mutation or binding of the agonist naltriben:
2. 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:
Permeation of K+ ions through the TRPM7-N1098Qopen channel under the applied voltage of 600 mV. The K+ ions permeating the lower gate and/or the Y1085 level are shown as orange, purple, blue, and green spheres. Non-permeating K+ ions are shown as grey spheres. 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 45 ns: