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- PDB-8u3l: TRPV1 in nanodisc bound with empty vanilloid binding pocket at 25C -

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Basic information

Entry
Database: PDB / ID: 8u3l
TitleTRPV1 in nanodisc bound with empty vanilloid binding pocket at 25C
ComponentsTransient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / TRPV1 in nanodisc bound with empty vanilloid binding pocket at 25C
Function / homology
Function and homology information


response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain / urinary bladder smooth muscle contraction / TRP channels ...response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain / urinary bladder smooth muscle contraction / TRP channels / smooth muscle contraction involved in micturition / fever generation / thermoception / detection of temperature stimulus involved in thermoception / cellular response to acidic pH / negative regulation of systemic arterial blood pressure / response to pH / dendritic spine membrane / chloride channel regulator activity / glutamate secretion / monoatomic cation transmembrane transporter activity / negative regulation of heart rate / cellular response to ATP / response to pain / temperature homeostasis / cellular response to alkaloid / diet induced thermogenesis / cellular response to cytokine stimulus / ligand-gated monoatomic ion channel activity / behavioral response to pain / intracellularly gated calcium channel activity / detection of temperature stimulus involved in sensory perception of pain / negative regulation of mitochondrial membrane potential / calcium ion import across plasma membrane / monoatomic cation channel activity / extracellular ligand-gated monoatomic ion channel activity / sensory perception of pain / phosphatidylinositol binding / GABA-ergic synapse / phosphoprotein binding / microglial cell activation / cellular response to nerve growth factor stimulus / cellular response to growth factor stimulus / calcium ion transmembrane transport / calcium channel activity / lipid metabolic process / response to peptide hormone / calcium ion transport / positive regulation of nitric oxide biosynthetic process / transmembrane signaling receptor activity / sensory perception of taste / cellular response to tumor necrosis factor / cellular response to heat / response to heat / positive regulation of cytosolic calcium ion concentration / monoatomic ion transmembrane transport / protein homotetramerization / postsynaptic membrane / calmodulin binding / 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 / identical protein 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
1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsArnold, W.R. / Julius, D. / Cheng, Y.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural basis of TRPV1 modulation by endogenous bioactive lipids.
Authors: William R Arnold / Adamo Mancino / Frank R Moss / Adam Frost / David Julius / Yifan Cheng /
Abstract: TRP ion channels are modulated by phosphoinositide lipids, but the underlying structural mechanisms remain unclear. The capsaicin- and heat-activated receptor, TRPV1, has served as a model for ...TRP ion channels are modulated by phosphoinositide lipids, but the underlying structural mechanisms remain unclear. The capsaicin- and heat-activated receptor, TRPV1, has served as a model for deciphering lipid modulation, which is relevant to understanding how pro-algesic agents enhance channel activity in the setting of inflammatory pain. Identification of a pocket within the TRPV1 transmembrane core has provided initial clues as to how phosphoinositide lipids bind to and regulate the channel. Here we show that this regulatory pocket in rat TRPV1 can accommodate diverse lipid species, including the inflammatory lipid lysophosphatidic acid, whose actions are determined by their specific modes of binding. Furthermore, we show that an empty-pocket channel lacking an endogenous phosphoinositide lipid assumes an agonist-like state, even at low temperature, substantiating the concept that phosphoinositide lipids serve as negative TRPV1 modulators whose ejection from the binding pocket is a critical step toward activation by thermal or chemical stimuli.
History
DepositionSep 7, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2024Provider: repository / Type: Initial release
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Revision 1.1May 15, 2024Group: Database references / Category: citation / citation_author
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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
D: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)373,4609
Polymers370,6174
Non-polymers2,8435
Water724
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 / TrpV1 / Capsaicin receptor / Osm-9-like TRP channel 1 / OTRPC1 / Vanilloid receptor 1 / Vanilloid ...TrpV1 / Capsaicin receptor / Osm-9-like TRP channel 1 / OTRPC1 / Vanilloid receptor 1 / Vanilloid receptor type 1-like


Mass: 92654.172 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Trpv1, Vr1, Vr1l / Production host: Homo sapiens (human) / References: UniProt: O35433
#2: Chemical
ChemComp-3PH / 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / PHOSPHATIDIC ACID


Mass: 704.998 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C39H77O8P
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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 in nanodisc with empty vanilloid binding pocket at 25C
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.688 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 2.1 mg/ml / Embedding 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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 39183 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00317900
ELECTRON MICROSCOPYf_angle_d0.46324204
ELECTRON MICROSCOPYf_dihedral_angle_d3.7812436
ELECTRON MICROSCOPYf_chiral_restr0.0352708
ELECTRON MICROSCOPYf_plane_restr0.0022988

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