On July 23rd 2018, a research paper titled “The conformational wave in capsaicin activation of Transient Receptor Potential Vanilloid 1 ion channel” has been published in Nature Communications from Dr. Fan Yang’s group. In this study, with a combination of fluorescent unnatural amino acid imaging, computational structural modeling and single-channel patch-clamp recording, they observed the conformational wave induced by capsaicin binding to its receptor TRPV1 ion channel, unveiling the conformational dynamics in this channel.
The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. In this study, Dr. Yang’s group report that reducing the temperature towards the freezing point led to channel closure even in the presence of saturating capsaicin. They further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling and rate-equilibrium linear free-energy relationships analysis (Φ-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. They observed that capsaicin initiates a conformational wave that propagates through the S4-S5 linker towards the S6 bundle and finally reaching the selectivity filter. Therefore, their study provides a temporal mechanism for capsaicin activation of TRPV1.
TRPV1 channel is an important target for analgesic drugs, so understanding its ligand gating mechanism lays a solid ground for drug development targeting this channel in future. The research strategy employed in this study is also generally applicable to study the conformational dynamics in other ion channels, which promotes the transition from study of a static state to dynamic conformation waves in structural biology.
This study is a collaboration between Zhejiang University and University of California at Davis. Dr. Fan Yang from the Department of Biophysics, Zhejiang University School of Medicine, Dr Xian Xiao from the Institute for Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University and Dr. Bo Hyun Lee from University of California at Davis are co-first authors. Dr. Fan Yang and Dr. Jie Zheng from University of California at Davis are co-corresponding authors. Zhejiang University School of Medicine is listed as the first author institution. Dr. Wei Yang from Zhejiang University School of Medicine, Simon Vu and Dr. Vladimir Yarov-Yarovoy from University of California at Davis are co-authors of this study. This wok has been supported by the Natural Science Foundation of China, Young Thousand Talent Program of China, American Heart Association and National Institutes of Health, USA.
For more detailed description of this study, please visit Dr. Fan Yang’s blog:
http://blog.sciencenet.cn/home.php?mod=space&uid=796366&do=blog&id=1125555
