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- PDB-7xem: Cholesterol bound state of mTRPV2 -

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Basic information

Entry
Database: PDB / ID: 7xem
TitleCholesterol bound state of mTRPV2
ComponentsTransient receptor potential cation channel subfamily V member 2
KeywordsSTRUCTURAL PROTEIN / mTRPV2 / chloesterol
Function / homology
Function and homology information


growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / axonal growth cone / positive regulation of axon extension / monoatomic cation channel activity / calcium channel activity / melanosome / positive regulation of cold-induced thermogenesis ...growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / axonal growth cone / positive regulation of axon extension / monoatomic cation channel activity / calcium channel activity / melanosome / positive regulation of cold-induced thermogenesis / cell body / axon / cell surface / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / 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 2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsSu, N.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32122040 China
CitationJournal: Nat Chem Biol / Year: 2023
Title: Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands.
Authors: Nannan Su / Wenxuan Zhen / Heng Zhang / Lingyi Xu / Yitian Jin / Xiaoying Chen / Cheng Zhao / Qinrui Wang / Xinyan Wang / Shaowei Li / Han Wen / Wei Yang / Jiangtao Guo / Fan Yang /
Abstract: The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being ...The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being identified, whether and how TRPV2 is regulated by endogenous lipids remains elusive. Here, we report an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2, with a 'head down, tail up' configuration, resolved at 3.2 Å using cryo-EM. Cholesterol binding antagonizes ligand activation of TRPV2, which is removed from VBP by methyl-β-cyclodextrin (MβCD) as resolved at 2.9 Å. We also observed that estradiol (E2) potentiated TRPV2 activation by 2-aminoethoxydiphenyl borate (2-APB), a classic tool compound for TRP channels. Our cryo-EM structures (resolved at 2.8-3.3 Å) further suggest how E2 disturbed cholesterol binding and how 2-APB bound within the VBP with E2 or without both E2 and endogenous cholesterol, respectively. Therefore, our study has established the structural basis for ligand recognition of the inhibitory endogenous cholesterol and excitatory exogenous 2-APB in TRPV2.
History
DepositionMar 31, 2022Deposition site: PDBJ / Processing site: PDBJ
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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 2
B: Transient receptor potential cation channel subfamily V member 2
C: Transient receptor potential cation channel subfamily V member 2
D: Transient receptor potential cation channel subfamily V member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)345,7798
Polymers344,2334
Non-polymers1,5474
Water724
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Transient receptor potential cation channel subfamily V member 2 / TrpV2 / Growth factor-regulated calcium channel / GRC / Osm-9-like TRP channel 2 / OTRPC2


Mass: 86058.195 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trpv2, Grc / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9WTR1
#2: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
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: complex of mTRPV2 and cholesterol / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK 293
Buffer solutionpH: 7.4
SpecimenConc.: 4 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 8 sec. / Electron dose: 62 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 40899 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00420612
ELECTRON MICROSCOPYf_angle_d0.6727996
ELECTRON MICROSCOPYf_dihedral_angle_d5.4252728
ELECTRON MICROSCOPYf_chiral_restr0.0423176
ELECTRON MICROSCOPYf_plane_restr0.0043436

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