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- PDB-9pea: Cryo-EM structure of full-length human TRPV1 in complex with anal... -

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Basic information

Entry
Database: PDB / ID: 9pea
TitleCryo-EM structure of full-length human TRPV1 in complex with analgesic MSP20
ComponentsTransient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / transient receptor potential V family member 1 / TRP / channel / TRPV1 / TRP channels / analgesic / MSP20 / pain / analgesia / agonist / synthesis / vanilliod
Function / homology
Function and homology information


chemosensory behavior / response to capsazepine / temperature-gated ion channel activity / thermoception / excitatory extracellular ligand-gated monoatomic ion channel activity / dendritic spine membrane / cellular response to alkaloid / TRP channels / intracellularly gated calcium channel activity / cellular response to ATP ...chemosensory behavior / response to capsazepine / temperature-gated ion channel activity / thermoception / excitatory extracellular ligand-gated monoatomic ion channel activity / dendritic spine membrane / cellular response to alkaloid / TRP channels / intracellularly gated calcium channel activity / cellular response to ATP / detection of temperature stimulus involved in sensory perception of pain / calcium ion import across plasma membrane / voltage-gated calcium channel activity / cellular response to acidic pH / extracellular ligand-gated monoatomic ion channel activity / phosphatidylinositol binding / phosphoprotein binding / GABA-ergic synapse / calcium ion transmembrane transport / calcium channel activity / transmembrane signaling receptor activity / cellular response to heat / protein homotetramerization / calmodulin binding / cell surface receptor signaling pathway / postsynaptic membrane / 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
: / CHOLESTEROL / Chem-POV / TRIDECANE / Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsNeuberger, A. / Talyzina, I.A. / Romeo, I. / Aiello, F. / Maramai, S. / Alcaro, S. / Artese, A. / Brizzi, A. / Sobolevsky, A.I.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA206573 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS107253 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R37 NS083660 United States
CitationJournal: Nat Commun / Year: 2026
Title: Design, synthesis and structural mechanism of action of TRPV1 agonist MSP20 with long-lasting analgesic effect.
Authors: Arthur Neuberger / Isabella Romeo / Francesca Aiello / Alexey Alekseev / Samuele Maramai / Federica Pessina / Chiara Vagaggini / Federica Poggialini / Elena Dreassi / Maria Frosini / Aniello ...Authors: Arthur Neuberger / Isabella Romeo / Francesca Aiello / Alexey Alekseev / Samuele Maramai / Federica Pessina / Chiara Vagaggini / Federica Poggialini / Elena Dreassi / Maria Frosini / Aniello Schiano Moriello / Luciano De Petrocellis / Andrea Maria Morace / Carmela Belardo / Michela Perrone / Roozbe Bonsale / Livio Luongo / Sabatino Maione / Irina A Talyzina / Stefano Alcaro / Anna Artese / Antonella Brizzi / Alexander I Sobolevsky /
Abstract: Transient receptor potential vanilloid type-1 (TRPV1) channel is a polymodal receptor involved in pain perception and neuronal signalling that represents a promising target for the development of ...Transient receptor potential vanilloid type-1 (TRPV1) channel is a polymodal receptor involved in pain perception and neuronal signalling that represents a promising target for the development of analgesics and neuroprotective agents. In this study we implement a combination of computational techniques and targeted design of chemical libraries to discover benzothiophene-substituted TRPV1 agonists with high affinity and efficacy toward TRPV1. In vitro functional experiments show that prolonged or repeated exposure to these compounds induce calcium-dependent desensitization of TRPV1, making it insensitive to noxious stimuli. We solve a cryo-electron microscopy (cryo-EM) structure of human TRPV1 (hTRPV1) in complex with the most promising benzothiophene-substituted agonist MSP20. The structure reveals molecular details of MSP20 binding to the vanilloid site and a desensitized conformation of hTRPV1, characterized by the closed ion channel pore, α-helical C-terminus and distinct behaviour of annular lipids. Our in vivo experiments demonstrate that MSP20 exhibits robust and long-lasting antinociceptive activity with ex-vivo neuroprotective effects, supporting the perspective of benzothiophene-substituted vanilloids as future analgesics.
History
DepositionJul 1, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)520,23942
Polymers498,3014
Non-polymers21,93838
Water00
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

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Protein , 1 types, 4 molecules ABCD

#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: 124575.281 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPV1, VR1 / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: Q8NER1

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Non-polymers , 5 types, 38 molecules

#2: Chemical
ChemComp-A1CHV / 3-(1-benzothiophen-2-yl)-N-[(4-hydroxy-3-methoxyphenyl)methyl]propanamide


Mass: 341.424 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H19NO3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical...
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#4: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O
#5: Chemical
ChemComp-TRD / TRIDECANE / LIPID FRAGMENT


Mass: 184.361 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H28
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na

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Details

Has ligand of interestY
Has protein modificationY

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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: full-length human TRPV1 in complex with MSP20 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.50 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Human embryonic kidney 293 / Plasmid: pEG BacMam
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMtris(hydroxymethyl)aminomethane1
31 mMbeta-Mercaptoethanol1
40.01 %glyco-diosgenin1
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: human TRPV1
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 defocus max: 1600 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2.7 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 12312
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.2.1particle selection
4cryoSPARCv4.2.1CTF correction
12cryoSPARCv4.4.03D reconstruction
13PHENIX1.18model refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 324554
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 249242 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00639084
ELECTRON MICROSCOPYf_angle_d1.00970960
ELECTRON MICROSCOPYf_dihedral_angle_d13.55315688
ELECTRON MICROSCOPYf_chiral_restr0.1022760
ELECTRON MICROSCOPYf_plane_restr0.0085468

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