The University of Tokyo

University of Tsukuba

Japan Synchrotron Radiation Research Institute (JASRI)

Japan Science and Technology Agency (JST)

Japan Agency for Medical Research and Development (AMED)

Key achievements

・The research group carried out, for the first time in the world, the real-time observation of intramolecular motion of protein transient receptor potential (TRP) channels used to sense the heat and pain felt by humans and demonstrated that the motion is very small.

・The TRP channels bind to capsaicin, a constituent of hot pepper, and send signals through their clockwise twisting motion.

・Because the TRP channels are related to the mechanism of pain in humans, the achievement of this study is expected to contribute to the understanding of the mechanism of pain perception and the development of new pain relievers.

Abstract

A research group led by Professor Yuji Sasaki of Advanced Materials Science, Graduate School of Frontier Sciences, The University of Tokyo, has succeeded in the real-time observation of the intramolecular motion of TRP channels, which play a role in sending heat and pain signals, on the microsecond order for the first time in the world.

TRP channels, which consist of four subunits each having six transmembrane segments, are related to the responses to sensory stimuli in humans and various animal species. Their detailed structure has been clarified recently; their research has been actively pursued and TRP channels have been attracting considerable attention. When capsaicin, which activates the TRP channels, was added, the TRP channels opened up to allow the flow of ions while the channels twisted clockwise. In contrast, when a drug that inhibits the activity of TRP channels was added, the channels twisted counterclockwise. In addition, in the experiment using mutant TRP channels that do not react with capsaicin, a counterclockwise twisting motion that inhibited the channel motion was observed similarly to the case of adding a drug that inhibits their activity. As explained above, the research group has succeeded in observing, in real time, the dynamic clockwise and counterclockwise motions of TRP channels under various conditions. The diffusion constant of these motions was found to be extremely small (20-30 pm2/ms).

The research group used a diffracted X-ray tracking (DXT) method to detect the intramolecular dynamics of a molecule labeled with Au nanocrystals in a video of a single molecule. The experiment was carried out using BL40XU (Note 5) at a large synchrotron radiation facility, SPring-8, located at Nishiharima, Hyogo Prefecture. The DXT method is highly expected to contribute to the development of new technologies for drug discovery utilizing molecular motions, which has not been realized by the conventional determination of molecular structures and the structural analysis of reaction pockets. This achievement published in Journal of Physical Chemistry, an established international journal in physical chemistry, on 9th December 2020.

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