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- PDB-11cl: Structure of human TRPV1 in complex with Asivatrep -

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Basic information

Entry
Database: PDB / ID: 11cl
TitleStructure of human TRPV1 in complex with Asivatrep
ComponentsTransient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / Ion Channel / TRPV1 / Mavatrep / Asivatrep / JNJ-17203212 / CAY10448 / Small Molecule / Pain / Thermosensing / GDN / Antagonist
Function / homology
Function and homology information


chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / fever generation / detection of temperature stimulus involved in thermoception / thermoception ...chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / fever generation / detection of temperature stimulus involved in thermoception / thermoception / excitatory extracellular ligand-gated monoatomic ion channel activity / dendritic spine membrane / diet induced thermogenesis / TRP channels / cellular response to alkaloid / cellular response to ATP / intracellularly gated calcium channel activity / detection of temperature stimulus involved in sensory perception of pain / calcium ion import across plasma membrane / behavioral response to pain / voltage-gated calcium channel activity / cellular response to acidic pH / extracellular ligand-gated monoatomic ion channel activity / phosphatidylinositol binding / lipid metabolic process / phosphoprotein binding / GABA-ergic synapse / calcium ion transmembrane transport / calcium channel activity / transmembrane signaling receptor activity / cellular response to heat / sensory perception of taste / protein homotetramerization / calmodulin binding / postsynaptic membrane / cell surface receptor signaling pathway / negative regulation of transcription by RNA polymerase II / ATP binding / membrane / metal ion binding / 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
: / EICOSANE / Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.1 Å
AuthorsLopez, K.E. / Van Horn, W.D.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS119505 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM141933 United States
American Heart Association23POST1029540 United States
CitationJournal: bioRxiv / Year: 2026
Title: TRPV1 antagonism occurs through diverse structural mechanisms.
Authors: Kyle E Lopez / Audrey S Paduda / Matthew J Derrick / Wade D Van Horn /
Abstract: Transient receptor potential vanilloid 1 (TRPV1) ion channel mediates thermosensation and pain and is a target for non-addictive analgesics; however, clinical candidates have failed due to ...Transient receptor potential vanilloid 1 (TRPV1) ion channel mediates thermosensation and pain and is a target for non-addictive analgesics; however, clinical candidates have failed due to thermoregulatory side effects. Limited structural data for human TRPV1 (hTRPV1) bound to clinically relevant antagonists has constrained mechanistic insight. Using chemoinformatics-informed cryo-EM and BRET assays, we define the structural basis of antagonism across diverse chemotypes, including failed clinical compounds. A structure of hTRPV1 bound to 6-iodo-dihydrocapsaicin shows how a single substitution converts an agonist into an antagonist. Additional structures with Asivatrep, Mavatrep, and JNJ-17203212 reveal vanilloid pocket plasticity and divergent interaction networks, including lipid co-binding. Despite this diversity, antagonists converge on a conserved inhibited state, showing high potency is maintained across flexible binding modes. These findings redefine our understanding of hTRPV1 antagonism and illustrate how chemically diverse ligands stabilize an inhibited state in polymodal ion channels, laying groundwork for next-generation analgesics with improved safety.
History
DepositionFeb 17, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 3, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 1
C: Transient receptor potential cation channel subfamily V member 1
D: Transient receptor potential cation channel subfamily V member 1
B: Transient receptor potential cation channel subfamily V member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)500,22212
Polymers497,1264
Non-polymers3,0968
Water28816
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Transient receptor potential cation channel subfamily V member 1 / TrpV1 / Capsaicin receptor / Osm-9-like TRP channel 1 / OTRPC1 / Vanilloid receptor 1


Mass: 124281.469 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPV1, VR1 / Production host: Homo sapiens (human) / References: UniProt: Q8NER1
#2: Chemical
ChemComp-A1C8J / (2E)-N-{(1R)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl}-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide / Asivatrep


Mass: 491.475 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H22F5N3O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-LFA / EICOSANE / LIPID FRAGMENT


Mass: 282.547 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H42
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Tetrameric hTRPV1 in complex with Asivatrep / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.496528 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 GnTI-
Buffer solutionpH: 8
Buffer component
IDConc.NameBuffer-ID
120 mMTris-HCl1
2150 mMSodium Chloride1
31 mM2-Mercaptoethanol1
40.01 %Glyco-diosgeenin1
SpecimenConc.: 0.75 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.7 sec. / Electron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 40605
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
7UCSF ChimeraX1.11model fitting
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.21.2model refinement
14Coot0.9.8.93model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4879389
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 476551 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 11CN

11cn


Accession code: 11CN
Details: Used hTRPV1 in complex with Mavatrep as the starting model.
Source name: PDB / Type: experimental model

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