Transient receptor potential vanilloid 1(TRPV1)channel plays an important role in a wide range of phys-iological and pathological processes,and a comprehensive understanding of TRPV1 gating will create opportunities for therapeutic intervention.Recent incredible advances in cryo-electron microscopy(cryo-EM)have yielded high-resolution structures of all TRPV subtypes(TRPV1-6)and all of them share highly conserved six transmembrane(TM)domains(S1-S6).As revealed by the open structures ofTRPVl in the presence of a bound vanilloid agonist(capsaicin or resiniferatoxin),TM helices S1 to S4 form a bun-dle that remains quiescent during channel activation,highlighting differences in the gating mechanism of TRPV1 and voltage-gated ion channels.Here,however,we argue that the structural dynamics rather than quiescence of S1-S4 domains is necessary for capsaicin-mediated activation ofTRPV1.Using fluorescent unnatural amino acid(flUAA)incorporation and voltage-clamp fluorometry(VCF)analysis,we directly observed allostery of the S1-S4 bundle upon capsaicin binding.Covalent occupation of VCF-identified sites,single-channel recording,cell apoptosis analysis,and exploration of the role of PSFL828,a novel non-vanilloid agonist we identified,have collectively confirmed the essential role of this coordinated S1-S4 motility in capsaicin-mediated activation ofTRPV1.This study concludes that,in contrast to cryo-EM structural studies,vanilloid agonists are also required for S1-S4 movement during TRPV1 acti-vation.Redefining the gating process of vanilloid agonists and the discovery of new non-vanilloid ago-nists will allow the evaluation of new strategies aimed at the development of TRPV1 modulators.

Meng-Yang Sun;Xue Zhang;Peng-Cheng Yu;Di Liu;Yang Yang;Wen-Wen Cui;Xiao-Na Yang;Yun-Tao Lei;Xing-Hua Li;Wen-Hui Wang;Peng Cao;Heng-Shan Wang;Michael X.Zhu;Chang-Zhu Li;Rui Wang;Ying-Zhe Fan;Ye Yu

School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province,School of Basic Medical Sciences,Lanzhou University,Lanzhou 730000,China;Department of Pharmacology and Chemical Biology,Institute of Medical Sciences,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Department of Basic Medicine and Clinical Pharmacy,China Pharmaceutical University,Nanjing 210009,China;College of Bioscience and Biotechnology,Hunan Agricultural University,Changsha 410128,China;Hospital of Integrated Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China;State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources,Collaborative Innovation Center for Guangxi Ethnic Medicine,School of Chemistry and Pharmaceutical Sciences,Guangxi Normal University,Guilin 541004,China;Department of Integrative Biology and Pharmacology,McGovern Medical School,The University of Texas Health Science Center at Houston,Houston,TX 77030,USA;State Key Laboratory of Utilization of Woody Oil Resource,Hunan Academy of Forestry,Changsha 410004,China;Putuo Hospital,Shanghai University of Chinese Traditional Medicine,Shanghai 200062,China

科学通报（英文版）

[1]Meng-Yang Sun;Xue Zhang;Peng-Cheng Yu;Di Liu;Yang Yang;Wen-Wen Cui;Xiao-Na Yang;Yun-Tao Lei;Xing-Hua Li;Wen-Hui Wang;Peng Cao;Heng-Shan Wang;Michael X.Zhu;Chang-Zhu Li;Rui Wang;Ying-Zhe Fan;Ye Yu-.Vanilloid agonist-mediated activation of TRPV1 channels requires coordinated movement of the S1-S4 bundle rather than a quiescent state)[J].科学通报（英文版）,2022(10):1062-1076

Vanilloid,ofTRPVl,capsaicin,resiniferatoxin,ofTRPV1,flUAA,fluorometry,allostery,PSFL828,nists

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