Faculty, Staff and Student Publications
Language
English
Publication Date
1-27-2026
Journal
Cell Reports
DOI
10.1016/j.celrep.2025.116765
PMID
41447532
Abstract
TRPV1, a member of the transient receptor potential vanilloid subfamily, mediates nociception and thermoregulation. TRPV1-targeting analgesics frequently induce hyperthermia, underscoring the need for structural insights to guide the development of safer compounds. Here, we determined the structures of rat TRPV1 bound to the clinical candidate analgesics AMG517, AMG9810, and SB366791. AMG517 and AMG9810 are deeply situated within the S3-S4 interface of the vanilloid pocket, where they interact with residues from the S3-S6 helices, as well as the S4-S5 linker. These interactions induce local deformations in the TRP-box and lower S6 helix, accompanied by a modest rotation of the S1-S4 bundle, leading to partial dilation of the lower gate. The distinct allosteric changes of AMG517 and AMG9810, compared with the non-hyperthermic ligand SB366791, suggest a structural basis by which TRPV1-targeting analgesics influence thermoregulation and provide insights for designing safer analogs.
Keywords
TRPV Cation Channels, Animals, Analgesics, Rats, Hyperthermia, Protein Binding, Humans, Binding Sites, CP: Neuroscience, TRPV1, allosteric modulation, biased confomation, cryo-EM, hyperthermia, thermoregulation
Published Open-Access
yes
Recommended Citation
Gao, Yu-Hao; Huang, Yi-Zhe; Li, Zhao-Xing; et al., "Structures of TRPV1 Bound by Hyperthermia-Inducing Analgesics" (2026). Faculty, Staff and Student Publications. 6209.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6209
Graphical Abstract
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