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- EMDB-65639: Structure of rat TRPV1 in complex with SB-366791 -

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Basic information

Entry
Database: EMDB / ID: EMD-65639
TitleStructure of rat TRPV1 in complex with SB-366791
Map data
Sample
  • Complex: Cryo-EM structure of rat TRPV1 in complex with the analgesic drug SB-36679
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 1
  • Ligand: (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)prop-2-enamide
KeywordsTRPV1 / protein complex / TRANSPORT PROTEIN
Function / homology
Function and homology information


negative regulation of iodide transmembrane transport / negative regulation of establishment of blood-brain barrier / peptide secretion / sensory perception of mechanical stimulus / detection of temperature stimulus involved in thermoception / positive regulation of membrane depolarization / positive regulation of renal sodium excretion / response to capsazepine / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain ...negative regulation of iodide transmembrane transport / negative regulation of establishment of blood-brain barrier / peptide secretion / sensory perception of mechanical stimulus / detection of temperature stimulus involved in thermoception / positive regulation of membrane depolarization / positive regulation of renal sodium excretion / response to capsazepine / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain / positive regulation of sensory perception of pain / temperature-gated ion channel activity / smooth muscle contraction involved in micturition / TRP channels / fever generation / negative regulation of axon regeneration / diet induced thermogenesis / positive regulation of cardiac muscle cell differentiation / urinary bladder smooth muscle contraction / thermoception / response to pH / glutamate secretion / monoatomic cation transmembrane transporter activity / response to acidic pH / negative regulation of systemic arterial blood pressure / response to pain / excitatory extracellular ligand-gated monoatomic ion channel activity / dendritic spine membrane / positive regulation of urine volume / negative regulation of heart rate / cellular response to alkaloid / cellular response to cytokine stimulus / sensory perception of taste / temperature homeostasis / intracellularly gated calcium channel activity / cellular response to ATP / negative regulation of mitochondrial membrane potential / detection of temperature stimulus involved in sensory perception of pain / behavioral response to pain / calcium ion import across plasma membrane / positive regulation of vasoconstriction / monoatomic ion channel activity / ligand-gated monoatomic ion channel activity / monoatomic cation channel activity / cellular response to acidic pH / extracellular ligand-gated monoatomic ion channel activity / sensory perception of pain / phosphatidylinositol binding / axon terminus / positive regulation of excitatory postsynaptic potential / lipid metabolic process / sarcoplasmic reticulum / microglial cell activation / phosphoprotein binding / cellular response to tumor necrosis factor / cellular response to nerve growth factor stimulus / cellular response to growth factor stimulus / response to peptide hormone / GABA-ergic synapse / calcium ion transmembrane transport / calcium channel activity / positive regulation of nitric oxide biosynthetic process / calcium ion transport / transmembrane signaling receptor activity / cellular response to heat / response to heat / positive regulation of cytosolic calcium ion concentration / monoatomic ion transmembrane transport / protein homotetramerization / calmodulin binding / postsynaptic membrane / neuron projection / positive regulation of apoptotic process / external side of plasma membrane / neuronal cell body / dendrite / negative regulation of transcription by RNA polymerase II / ATP binding / membrane / metal ion binding / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeat profile. / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsChen X / Yu Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371289 China
CitationJournal: Cell Rep / Year: 2026
Title: Structures of TRPV1 bound by hyperthermia-inducing analgesics.
Authors: Yu-Hao Gao / Yi-Zhe Huang / Zhao-Xing Li / Xiao-Ying Chen / Chang-Yan Shao / Han-Wen Li / Bin Liu / Fán Yang / Mei-Rong Chen / Mei-Ling Lu / Michael X Zhu / Fan Yang / Yi-Bei Xiao / Ye Yu /
Abstract: TRPV1, a member of the transient receptor potential vanilloid subfamily, mediates nociception and thermoregulation. TRPV1-targeting analgesics frequently induce hyperthermia, underscoring the need ...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.
History
DepositionJul 31, 2025-
Header (metadata) releaseNov 26, 2025-
Map releaseNov 26, 2025-
UpdateMay 13, 2026-
Current statusMay 13, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65639.png

Downloads & links

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Map

FileDownload / File: emd_65639.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.107
Minimum - Maximum-0.54918504 - 0.8147074
Average (Standard dev.)0.0012552629 (±0.028171543)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_65639_half_map_1.map
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Half map: #1

Fileemd_65639_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of rat TRPV1 in complex with the analgesic drug...

EntireName: Cryo-EM structure of rat TRPV1 in complex with the analgesic drug SB-36679
Components
  • Complex: Cryo-EM structure of rat TRPV1 in complex with the analgesic drug SB-36679
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 1
  • Ligand: (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)prop-2-enamide

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Supramolecule #1: Cryo-EM structure of rat TRPV1 in complex with the analgesic drug...

SupramoleculeName: Cryo-EM structure of rat TRPV1 in complex with the analgesic drug SB-36679
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 1

MacromoleculeName: Transient receptor potential cation channel subfamily V member 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 99.514625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKWS HPQFEKGGGG SGGSAWSHPQ FEKEFKGLVD MEQRASLDSE ESESPPQENS CLDPPDRDPN CKPPPVKPHI FTTRSRTRL FGKGDSEEAS PLDCPYEEGG LASCPIITVS SVLTIQRPGD GPASVRPSSQ DSVSAGEKPP RLYDRRSIFD A VAQSNCQE ...String:
DYKDDDDKWS HPQFEKGGGG SGGSAWSHPQ FEKEFKGLVD MEQRASLDSE ESESPPQENS CLDPPDRDPN CKPPPVKPHI FTTRSRTRL FGKGDSEEAS PLDCPYEEGG LASCPIITVS SVLTIQRPGD GPASVRPSSQ DSVSAGEKPP RLYDRRSIFD A VAQSNCQE LESLLPFLQR SKKRLTDSEF KDPETGKTCL LKAMLNLHNG QNDTIALLLD VARKTDSLKQ FVNASYTDSY YK GQTALHI AIERRNMTLV TLLVENGADV QAAANGDFFK KTKGRPGFYF GELPLSLAAC TNQLAIVKFL LQNSWQPADI SAR DSVGNT VLHALVEVAD NTVDNTKFVT SMYNEILILG AKLHPTLKLE EITNRKGLTP LALAASSGKI GVLAYILQRE IHEP ECRHL SRKFTEWAYG PVHSSLYDLS CIDTCEKNSV LEVIAYSSSE TPNRHDMLLV EPLNRLLQDK WDRFVKRIFY FNFFV YCLY MIIFTAAAYY RPVEGLPPYK LKNTVGDYFR VTGEILSVSG GVYFFFRGIQ YFLQRRPSLK SLFVDSYSEI LFFVQS LFM LVSVVLYFSQ RKEYVASMVF SLAMGWTNML YYTRGFQQMG IYAVMIEKMI LRDLCRFMFV YLVFLFGFST AVVTLIE DG KNNSLPMEST PHKCRGSACK PGNSYNSLYS TCLELFKFTI GMGDLEFTEN YDFKAVFIIL LLAYVILTYI LLLNMLIA L MGETVNKIAQ ESKNIWKLQR AITILDTEKS FLKCMRKAFR SGKLLQVGFT PDGKDDYRWC FRVDEVNWTT WNTNVGIIN EDPGNCEGVK RTLSFSLRSG RVSGRNWKNF ALVPLLRDAS TRDRHATQQE EVQLKHYTGS LKPEDAEVFK DSMVPGEK

UniProtKB: Transient receptor potential cation channel subfamily V member 1

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Macromolecule #2: (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)prop-2-enamide

MacromoleculeName: (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)prop-2-enamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: ZEI
Molecular weightTheoretical: 287.741 Da
Chemical component information

ChemComp-ZEI:
(2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)prop-2-enamide

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8 / Details: 20 mM Hepes, 150 mM NaCl
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average exposure time: 4.5 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 15491
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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