9W4N

Structure of rat TRPV1 in complex with SB-366791

Summary for 9W4N

• Entry DOI: 10.2210/pdb9w4n/pdb
• EMDB information: 65639
• Descriptor: Transient receptor potential cation channel subfamily V member 1, (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)prop-2-enamide (2 entities in total)
• Functional Keywords: trpv1, protein complex, transport protein
• Biological source: Rattus norvegicus (Norway rat)
• Total number of polymer chains: 4
• Total formula weight: 399209.46

Authors

Chen, X.,Yu, Y. (deposition date: 2025-07-31, release date: 2025-11-26, Last modification date: 2026-05-13)

Primary citation

Gao, Y.H.,Huang, Y.Z.,Li, Z.X.,Chen, X.Y.,Shao, C.Y.,Li, H.W.,Liu, B.,Yang, F.,Chen, M.R.,Lu, M.L.,Zhu, M.X.,Yang, F.,Xiao, Y.B.,Yu, Y.
Structures of TRPV1 bound by hyperthermia-inducing analgesics.
Cell Rep, 45:116765-116765, 2026

PubMed 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.

PubMed: 41447532
DOI: 10.1016/j.celrep.2025.116765

Experimental method

ELECTRON MICROSCOPY (3.25 Å)