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- PDB-8x94: Structure of human TRPV1 in complex with antagonist --protein pur... -

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Basic information

Entry
Database: PDB / ID: 8x94
TitleStructure of human TRPV1 in complex with antagonist --protein purified without CHS
ComponentsTransient receptor potential cation channel subfamily V member 1,Green fluorescent protein
KeywordsMEMBRANE PROTEIN / channel
Function / homology
Function and homology information


chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / 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 ...chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / 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 / cellular response to acidic pH / dendritic spine membrane / TRP channels / diet induced thermogenesis / cellular response to alkaloid / cellular response to ATP / detection of temperature stimulus involved in sensory perception of pain / intracellularly gated calcium channel activity / behavioral response to pain / calcium ion import across plasma membrane / voltage-gated calcium channel activity / extracellular ligand-gated monoatomic ion channel activity / phosphatidylinositol binding / phosphoprotein binding / calcium ion transmembrane transport / GABA-ergic synapse / calcium channel activity / lipid metabolic process / transmembrane signaling receptor activity / sensory perception of taste / cellular response to heat / protein homotetramerization / postsynaptic membrane / calmodulin binding / cell surface receptor signaling pathway / negative regulation of transcription by RNA polymerase II / ATP binding / metal ion binding / membrane / 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 repeats (3 copies) / Ankyrin repeat profile. / 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 / : / Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.55 Å
AuthorsFan, J. / Lei, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21625201 China
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis of TRPV1 inhibition by SAF312 and cholesterol.
Authors: Junping Fan / Han Ke / Jing Lei / Jin Wang / Makoto Tominaga / Xiaoguang Lei /
Abstract: Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive ...Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive antagonist of TRPV1 and shows promising potential in treating ocular surface pain. However, the precise mechanism by which SAF312 inhibits TRPV1 remains poorly understood. Here, we present the cryo-EM structure of human TRPV1 in complex with SAF312, elucidating the structural foundation of its antagonistic effects on TRPV1. SAF312 binds to the vanilloid binding pocket, preventing conformational changes in S4 and S5 helices, which are essential for channel gating. Unexpectedly, a putative cholesterol was found to contribute to SAF312's inhibition. Complemented by mutagenesis experiments and molecular dynamics simulations, our research offers substantial mechanistic insights into the regulation of TRPV1 by SAF312, highlighting the interplay between the antagonist and cholesterol in modulating TRPV1 function. This work not only expands our understanding of TRPV1 inhibition by SAF312 but also lays the groundwork for further developments in the design and optimization of TRPV1-related therapies.
History
DepositionNov 29, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
Revision 1.0Aug 14, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.1Aug 21, 2024Group: Data collection / Database references / Category: citation / em_admin
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Revision 1.2Jul 23, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
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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,Green fluorescent protein
B: Transient receptor potential cation channel subfamily V member 1,Green fluorescent protein
C: Transient receptor potential cation channel subfamily V member 1,Green fluorescent protein
D: Transient receptor potential cation channel subfamily V member 1,Green fluorescent protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)503,95912
Polymers501,1914
Non-polymers2,7688
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 125297.734 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: The section (840-842) is the cloning site.The domain (843-850) is PreScission Site.The domain (851-1084) is corresponding to this sfGFP (462-695 amino acids, GenBank: ALP48449.1). The domain ...Details: The section (840-842) is the cloning site.The domain (843-850) is PreScission Site.The domain (851-1084) is corresponding to this sfGFP (462-695 amino acids, GenBank: ALP48449.1). The domain (1085-1112) is the expression Tag.
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: TRPV1, VR1 / Production host: Homo sapiens (human) / References: UniProt: Q8NER1
#2: Chemical
ChemComp-EZI / 4-(7-Hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)benzonitrile / Vanilloid receptor antagonist 1 / Libvatrep


Mass: 305.331 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H15N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
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: TRPV1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.36 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 183350 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00317752
ELECTRON MICROSCOPYf_angle_d0.51824024
ELECTRON MICROSCOPYf_dihedral_angle_d4.2092340
ELECTRON MICROSCOPYf_chiral_restr0.0362684
ELECTRON MICROSCOPYf_plane_restr0.0052956

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