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Structures of TRPV1 bound by hyperthermia-inducing analgesics
Yu-Hao Gao1, Yi-Zhe Huang1, Zhao-Xing Li2
1Department of Basic Medicine, Schools of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Cell Reports
|December 25, 2025
Summary
Structural insights reveal how TRPV1-targeting analgesics like AMG517 and AMG9810 bind to the TRPV1 channel. This binding influences thermoregulation, offering a basis for developing safer pain-relief medications.
Area of Science:
- Structural biology
- Neuroscience
- Pharmacology
Background:
- Transient receptor potential vanilloid 1 (TRPV1) channels are key mediators of pain and body temperature regulation.
- TRPV1-targeting drugs, while effective analgesics, often cause hyperthermia, limiting their clinical use.
Purpose of the Study:
- To elucidate the structural mechanisms underlying the interaction of TRPV1 with specific analgesic compounds.
- To provide insights for the rational design of safer TRPV1-targeting analgesics with reduced hyperthermic side effects.
Main Methods:
- Determined the cryo-electron microscopy structures of rat TRPV1 in complex with AMG517, AMG9810, and SB366791.
- Analyzed ligand-induced structural changes in the TRPV1 channel, focusing on the vanilloid binding pocket and gating mechanisms.
Main Results:
- AMG517 and AMG9810 bind deep within the S3-S4 interface of the vanilloid pocket, inducing local structural deformations and partial opening of the lower gate.
- SB366791, a non-hyperthermic ligand, induces distinct allosteric changes compared to AMG517 and AMG9810.
- The observed structural differences correlate with the hyperthermic effects of the respective ligands.
Conclusions:
- The study reveals distinct binding modes and allosteric effects of TRPV1-targeting analgesics.
- These findings provide a structural foundation for understanding how TRPV1 ligands influence thermoregulation.
- The insights gained can guide the development of novel TRPV1 analgesics with improved safety profiles.
Keywords:
CP: NeuroscienceTRPV1allosteric modulationbiased confomationcryo-EMhyperthermiathermoregulationMore Related Videos
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