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- PDB-7e4t: Human TRPC5 apo state structure at 3 angstrom -

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Basic information

Entry
Database: PDB / ID: 7e4t
TitleHuman TRPC5 apo state structure at 3 angstrom
ComponentsShort transient receptor potential channel 5
KeywordsMETAL TRANSPORT / TRPC5 / trpc
Function / homology
Function and homology information


regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / cation channel complex / inositol 1,4,5 trisphosphate binding / actinin binding / TRP channels / clathrin binding ...regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / cation channel complex / inositol 1,4,5 trisphosphate binding / actinin binding / TRP channels / clathrin binding / positive regulation of axon extension / regulation of cytosolic calcium ion concentration / calcium channel complex / positive regulation of neuron differentiation / positive regulation of peptidyl-threonine phosphorylation / calcium ion transmembrane transport / calcium channel activity / neuron differentiation / calcium ion transport / nervous system development / actin binding / ATPase binding / positive regulation of cytosolic calcium ion concentration / growth cone / neuron apoptotic process / neuronal cell body / dendrite / positive regulation of cell population proliferation / plasma membrane
Similarity search - Function
Transient receptor potential channel, canonical 5 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeat / Ankyrin repeats (3 copies) / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential channel, canonical 5 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeat / Ankyrin repeats (3 copies) / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Chem-POV / PHOSPHATIDYLETHANOLAMINE / CHOLESTEROL HEMISUCCINATE / Chem-YZY / Short transient receptor potential channel 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsChen, L. / Song, K. / Wei, M. / Guo, W.
Funding support China, 4items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2016YFA0502004 China
National Natural Science Foundation of China (NSFC)31622021 China
National Science Foundation (NSF, China)91857000 China
National Science Foundation (NSF, China)31821091 China
CitationJournal: Elife / Year: 2021
Title: Structural basis for human TRPC5 channel inhibition by two distinct inhibitors.
Authors: Kangcheng Song / Miao Wei / Wenjun Guo / Li Quan / Yunlu Kang / Jing-Xiang Wu / Lei Chen /
Abstract: TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. ...TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.
History
DepositionFeb 15, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Short transient receptor potential channel 5
B: Short transient receptor potential channel 5
C: Short transient receptor potential channel 5
D: Short transient receptor potential channel 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)366,11928
Polymers355,3944
Non-polymers10,72524
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area46920 Å2
ΔGint-498 kcal/mol
Surface area119150 Å2

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Short transient receptor potential channel 5 / TrpC5 / Transient receptor protein 5 / hTRP5


Mass: 88848.578 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPC5, TRP5 / Production host: Homo sapiens (human) / References: UniProt: Q9UL62

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Non-polymers , 6 types, 24 molecules

#2: Chemical
ChemComp-PTY / PHOSPHATIDYLETHANOLAMINE


Mass: 734.039 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C40H80NO8P / Comment: phospholipid*YM
#3: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#4: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H50O4
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#7: Chemical
ChemComp-YZY / (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate


Mass: 594.949 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C37H70O5

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Details

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: human transient receptor potential channel 5 tetramer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29156 / Symmetry type: POINT

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