Agonist and antagonist diverted twisting motions of single TRPV1 channel [article]

Shoko Fujimura, Kazuhiro Mio, Masahiro Kuramochi, Hiroshi Sekiguchi, Ikezaki Keigo, Muneyo Mio, Kowit Hengphasatporn, Yasuteru Shigeta, Tai Kubo, Yuji C. Sasaki
2020 bioRxiv   pre-print
Transient receptor potential vanilloid type 1 (TRPV1) channels are activated by heat, vanilloids, and extracellular protons. Cryo-EM has revealed various conformations of TRPV1, and these structures suggest an intramolecular twisting motion in response to ligand binding. However, limited experimental data support this observation. Here we analyzed the intramolecular motion of TRPV1 using diffracted X-ray tracking (DXT). DXT analyzes trajectories of Laue spots generated from attached gold
more » ... ttached gold nanocrystals, and provides picometer spatial and microsecond time scale information about intramolecular motion. We observed that both an agonist and a competitive antagonist evoked rotating bias in TRPV1, though these biases were in opposing directions. Furthermore, the rotational bias generated by capsaicin was reversed between the wild type and the capsaicin-insensitive Y511A mutant. Our findings bolster the understanding of the mechanisms used activation and modulation of TRP channels, and this knowledge can be exploited for pharmacological usage such as inhibitor design.
doi:10.1101/2020.08.18.255109 fatcat:tlko4wrowvc5tinqapuslp2tb4