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- PDB-7rqw: Cryo-EM structure of the full-length TRPV1 with RTx at 4 degrees ... -

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Basic information

Entry
Database: PDB / ID: 7rqw
TitleCryo-EM structure of the full-length TRPV1 with RTx at 4 degrees Celsius, in an open state, class III
ComponentsTransient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / ligand-gating ion channel
Function / homology
Function and homology information


negative regulation of establishment of blood-brain barrier / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / cellular response to temperature stimulus / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / TRP channels / smooth muscle contraction involved in micturition ...negative regulation of establishment of blood-brain barrier / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / cellular response to temperature stimulus / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / TRP channels / smooth muscle contraction involved in micturition / fever generation / urinary bladder smooth muscle contraction / detection of temperature stimulus involved in thermoception / thermoception / cellular response to acidic pH / negative regulation of systemic arterial blood pressure / response to pH / chloride channel regulator activity / dendritic spine membrane / glutamate secretion / monoatomic cation transmembrane transporter activity / negative regulation of heart rate / ligand-gated monoatomic ion channel activity / response to pain / temperature homeostasis / diet induced thermogenesis / cellular response to alkaloid / cellular response to ATP / cellular response to cytokine stimulus / detection of temperature stimulus involved in sensory perception of pain / intracellularly gated calcium channel activity / behavioral response to 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 / phosphoprotein binding / microglial cell activation / response to peptide hormone / cellular response to nerve growth factor stimulus / GABA-ergic synapse / calcium ion transmembrane transport / cellular response to growth factor stimulus / calcium channel activity / lipid metabolic process / positive regulation of nitric oxide biosynthetic process / cellular response to tumor necrosis factor / calcium ion transport / transmembrane signaling receptor activity / sensory perception of taste / cellular response to heat / positive regulation of cytosolic calcium ion concentration / response to heat / 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 / metal ion binding / identical protein 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
resiniferatoxin / Chem-6OU / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 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: 3.11 Å
AuthorsKwon, D.H. / Suo, Y. / Lee, S.-Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35NS097241 United States
CitationJournal: Nat Commun / Year: 2022
Title: Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis.
Authors: Do Hoon Kwon / Feng Zhang / Justin G Fedor / Yang Suo / Seok-Yong Lee /
Abstract: Single particle cryo-EM often yields multiple protein conformations within a single dataset, but experimentally deducing the temporal relationship of these conformers within a conformational ...Single particle cryo-EM often yields multiple protein conformations within a single dataset, but experimentally deducing the temporal relationship of these conformers within a conformational trajectory is not trivial. Here, we use thermal titration methods and cryo-EM in an attempt to obtain temporal resolution of the conformational trajectory of the vanilloid receptor TRPV1 with resiniferatoxin (RTx) bound. Based on our cryo-EM ensemble analysis, RTx binding to TRPV1 appears to induce intracellular gate opening first, followed by selectivity filter dilation, then pore loop rearrangement to reach the final open state. This apparent conformational wave likely arises from the concerted, stepwise, additive structural changes of TRPV1 over many subdomains. Greater understanding of the RTx-mediated long-range allostery of TRPV1 could help further the therapeutic potential of RTx, which is a promising drug candidate for pain relief associated with advanced cancer or knee arthritis.
History
DepositionAug 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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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
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)409,32724
Polymers394,8794
Non-polymers14,44820
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
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: 98719.758 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-6EU / resiniferatoxin / RTX


Mass: 628.708 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C37H40O9 / Comment: toxin*YM
#3: Chemical
ChemComp-PCW / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / (Z,Z)-4-HYDROXY-N,N,N-TRIMETHYL-10-OXO-7-[(1-OXO-9-OCTADECENYL)OXY]-3,5,9-TRIOXA-4-PHOSPHAHEPTACOS-18-EN-1-AMINIUM-4-OXIDE


Mass: 787.121 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C44H85NO8P / Comment: DOPC, phospholipid*YM
#4: Chemical
ChemComp-LBN / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / (2R)-2-[(9Z)-9-Octadecenoyloxy]-3-(palmitoyloxy)propyl 2-(trimethylammonio)ethyl phosphate


Mass: 760.076 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#5: Chemical
ChemComp-6OU / [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate


Mass: 717.996 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C39H76NO8P / Comment: phospholipid*YM
Has ligand of interestN
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: Transient receptor potential cation channel subfamily V member 1
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.4 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameBuffer-ID
120 mMHEPES1
2150 mMsodium chloride1
SpecimenConc.: 0.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K

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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 magnification: 81000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 4 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2427
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansWidth: 5760 / Height: 4092

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
2Latitude1image acquisition
4Gctf1.06CTF correction
7PHENIX1.18.2model fitting
9RELION3.1.0initial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.18.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2700
3D reconstructionResolution: 3.11 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 107183 / Symmetry type: POINT
Atomic model buildingB value: 140 / Protocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 7LP9

7lp9


Pdb chain-ID: A / Accession code: 7LP9 / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00516980
ELECTRON MICROSCOPYf_angle_d0.72723092
ELECTRON MICROSCOPYf_dihedral_angle_d9.642368
ELECTRON MICROSCOPYf_chiral_restr0.0372644
ELECTRON MICROSCOPYf_plane_restr0.0032876

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