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- EMDB-71555: Cryo-EM structure of full-length human TRPV1 in complex with anal... -

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Basic information

Entry
Database: EMDB / ID: EMD-71555
TitleCryo-EM structure of full-length human TRPV1 in complex with analgesic MSP20
Map data
Sample
  • Complex: full-length human TRPV1 in complex with MSP20
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 1
  • Ligand: 3-(1-benzothiophen-2-yl)-N-[(4-hydroxy-3-methoxyphenyl)methyl]propanamide
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CHOLESTEROL
  • Ligand: TRIDECANE
  • Ligand: SODIUM ION
Keywordstransient receptor potential V family member 1 / TRP / channel / TRPV1 / TRP channels / analgesic / MSP20 / pain / analgesia / MEMBRANE PROTEIN / 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
Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsNeuberger A / Talyzina IA / Romeo I / Aiello F / Maramai S / Alcaro S / Artese A / Brizzi A / Sobolevsky AI
Funding support United States, 4 items
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, 2025-
Header (metadata) releaseJul 22, 2026-
Map releaseJul 22, 2026-
UpdateJul 22, 2026-
Current statusJul 22, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71555.png

Downloads & links

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Map

FileReleased
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.29548538 - 0.50284445
Average (Standard dev.)0.0013424588 (±0.01199523)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_71555_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_71555_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : full-length human TRPV1 in complex with MSP20

EntireName: full-length human TRPV1 in complex with MSP20
Components
  • Complex: full-length human TRPV1 in complex with MSP20
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 1
  • Ligand: 3-(1-benzothiophen-2-yl)-N-[(4-hydroxy-3-methoxyphenyl)methyl]propanamide
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CHOLESTEROL
  • Ligand: TRIDECANE
  • Ligand: SODIUM ION

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Supramolecule #1: full-length human TRPV1 in complex with MSP20

SupramoleculeName: full-length human TRPV1 in complex with MSP20 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 500 KDa

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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: Homo sapiens (human)
Molecular weightTheoretical: 124.575281 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTSKKWSSTD LGAAADPLQK DTCPDPLDGD PNSRPPPAKP QLSTAKSRTR LFGKGDSEEA FPVDCPHEEG ELDSCPTITV SPVITIQRP GDGPTGARLL SQDSVAASTE KTLRLYDRRS IFEAVAQNNC QDLESLLLFL QKSKKHLTDN EFKDPETGKT C LLKAMLNL ...String:
MTSKKWSSTD LGAAADPLQK DTCPDPLDGD PNSRPPPAKP QLSTAKSRTR LFGKGDSEEA FPVDCPHEEG ELDSCPTITV SPVITIQRP GDGPTGARLL SQDSVAASTE KTLRLYDRRS IFEAVAQNNC QDLESLLLFL QKSKKHLTDN EFKDPETGKT C LLKAMLNL HDGQNTTIPL LLEIARQTDS LKELVNASYT DSYYKGQTAL HIAIERRNMA LVTLLVENGA DVQAAAHGDF FK KTKGRPG FYFGELPLSL AACTNQLGIV KFLLQNSWQT ADISARDSVG NTVLHALVEV ADNTADNTKF VTSMYNEILM LGA KLHPTL KLEELTNKKG MTPLALAAGT GKIGVLAYIL QREIQEPECR HLSRKFTEWA YGPVHSSLYD LSCIDTCEKN SVLE VIAYS SSETPNRHDM LLVEPLNRLL QDKWDRFVKR IFYFNFLVYC LYMIIFTMAA YYRPVDGLPP FKMEKTGDYF RVTGE ILSV LGGVYFFFRG IQYFLQRRPS MKTLFVDSYS EMLFFLQSLF MLATVVLYFS HLKEYVASMV FSLALGWTNM LYYTRG FQQ MGIYAVMIEK MILRDLCRFM FVYIVFLFGF STAVVTLIED GKNDSLPSES TSHRWRGPAC RPPDSSYNSL YSTCLEL FK FTIGMGDLEF TENYDFKAVF IILLLAYVIL TYILLLNMLI ALMGETVNKI AQESKNIWKL QRAITILDTE KSFLKCMR K AFRSGKLLQV GYTPDGKDDY RWCFRVDEVN WTTWNTNVGI INEDPGNCEG VKRTLSFSLR SSRVSGRHWK NFALVPLLR EASARDRQSA QPEEVYLRQF SGSLKPEDAE VFKSPAASGE KLVPRGSAAA AVSKGEELFT GVVPILVELD GDVNGHKFSV SGEGEGDAT YGKLTLKFIC TTGKLPVPWP TLVTTLTYGV QCFSRYPDHM KQHDFFKSAM PEGYVQERTI FFKDDGNYKT R AEVKFEGD TLVNRIELKG IDFKEDGNIL GHKLEYNYNS HNVYIMADKQ KNGIKVNFKI RHNIEDGSVQ LADHYQQNTP IG DGPVLLP DNHYLSTQSK LSKDPNEKRD HMVLLEFVTA AGITLGMDEL YKSGLRSWSH PQFEK

UniProtKB: Transient receptor potential cation channel subfamily V member 1

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Macromolecule #2: 3-(1-benzothiophen-2-yl)-N-[(4-hydroxy-3-methoxyphenyl)methyl]pro...

MacromoleculeName: 3-(1-benzothiophen-2-yl)-N-[(4-hydroxy-3-methoxyphenyl)methyl]propanamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1CHV
Molecular weightTheoretical: 341.424 Da

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Macromolecule #3: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 3 / Number of copies: 24 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: TRIDECANE

MacromoleculeName: TRIDECANE / type: ligand / ID: 5 / Number of copies: 4 / Formula: TRD
Molecular weightTheoretical: 184.361 Da
Chemical component information

ChemComp-TRD:
TRIDECANE

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Macromolecule #6: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 6 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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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

Concentration3 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMtris(hydroxymethyl)aminomethane
1.0 mMbeta-Mercaptoethanol
0.01 %glyco-diosgenin
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Detailshuman TRPV1

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 12312 / Average exposure time: 2.7 sec. / Average electron dose: 60.0 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: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 324554
CTF correctionSoftware - Name: cryoSPARC (ver. v4.2.1) / Type: NONE
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.4.0) / Number images used: 249242
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-9pea:
Cryo-EM structure of full-length human TRPV1 in complex with analgesic MSP20

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