Structure of human TRPM8 channel

<p>This repository includes the following source datasets:</p> <p><strong>1. modeling.zip</strong><br> Modeling of icilin binding to HsTRPM8 (Figure 3e, 3f, 3g, 3h)<br>  - HsTRPM8-KX7_opt.pdb: original pose (Figure 3e, 3f)<br>  - HsTRPM8-KX7_opt_rotated.pdb: rotates pose (Figure 3g, 3h)</p> <p><strong>2. activation_assay.zip</strong><br> HsTRPM8 activation assay results (Figure 3i and Supplementary Figure 5)<br>  - HsTRPM8_activation_assay_results.pzf: GraphPad file with activation Assay results</p> <p><strong>3. Fr-TM.zip</strong><br> Structure-based multiple sequence alignment of TRPM channels (Supplementary Figure 4a)<br>  - Fr-TM_info.txt: description of procedure used to create alignment<br>  - TRPM_new_raw_pairwise_alignments.fas: raw pairwise alignment of new TRPM sequences to 6CO7 reference<br>  - TRPM_S6_restriction_site_aligned.fas: final multiple sequence alignment used to generate Supplementary Figure 4a</p> <p><strong>4. 3Dvar.zip</strong><br> HsTRPM8 3D Variability Analysis results (Supplementary Movie 1)<br>  - *.mrc files: composite maps with extreme frames for two analyzed components (aligned with focused MHR1/2 map)<br>  - *.pdb files: HsTRPM8 models fitted (MDFF) to above maps and used to generate Supplementary Movie 1</p> <p><strong>5. Supplementary_Movie_1.mp4</strong><br> Morphing between different conformations of HsTRPM8 resolved by 3D Variability analysis (Supplementary Movie 1).</p&gt

Structure of human TRPM8 channel

TRPM8 is a non-selective cation channel permeable to both monovalent and divalent cations that is activated by multiple factors, such as temperature, voltage, pressure, and changes in osmolality. It is a therapeutic target for anticancer drug development, and its modulators can be utilized for several pathological conditions. Here, we present a cryo-electron microscopy structure of a human TRPM8 channel in the closed state that was solved at 2.7 angstrom resolution. Our structure comprises the most complete model of the N-terminal pre-melastatin homology region. We also visualized several lipids that are bound by the protein and modeled how the human channel interacts with icilin. Analyses of pore helices in available TRPM structures showed that all these structures can be grouped into different closed, desensitized and open state conformations based on the register of the pore helix S6 which positions particular amino acid residues at the channel constriction.The cryo-EM structure of a human TRPM8 channel in the closed state is presented with insights into the N-terminal pre-melastatin homology region, lipid binding, and icilin binding