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- PDB-7dxg: Structure of SAR7334-bound TRPC6 at 2.9 angstrom -

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Basic information

Entry
Database: PDB / ID: 7dxg
TitleStructure of SAR7334-bound TRPC6 at 2.9 angstrom
ComponentsShort transient receptor potential channel 6
KeywordsMEMBRANE PROTEIN / TRPC6 / TRPC / FSGS / SAR7334 / channel
Function / homology
Function and homology information


positive regulation of ion transmembrane transporter activity / Role of second messengers in netrin-1 signaling / slit diaphragm / store-operated calcium channel activity / Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / cation channel complex / inositol 1,4,5 trisphosphate binding / positive regulation of calcium ion transport / TRP channels ...positive regulation of ion transmembrane transporter activity / Role of second messengers in netrin-1 signaling / slit diaphragm / store-operated calcium channel activity / Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / cation channel complex / inositol 1,4,5 trisphosphate binding / positive regulation of calcium ion transport / TRP channels / monoatomic cation transport / single fertilization / monoatomic cation channel activity / regulation of cytosolic calcium ion concentration / calcium ion transmembrane transport / calcium channel activity / positive regulation of cytosolic calcium ion concentration / protein homodimerization activity / membrane / plasma membrane / cytoplasm
Similarity search - Function
Transient receptor potential channel, canonical 6 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat ...Transient receptor potential channel, canonical 6 / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor ion channel II / Transient receptor potential channel, canonical / 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
Chem-98R / Chem-HOR / Chem-POV / CHOLESTEROL HEMISUCCINATE / Short transient receptor potential channel 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsChen, L. / 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: Neuron / Year: 2022
Title: Structural mechanism of human TRPC3 and TRPC6 channel regulation by their intracellular calcium-binding sites.
Authors: Wenjun Guo / Qinglin Tang / Miao Wei / Yunlu Kang / Jing-Xiang Wu / Lei Chen /
Abstract: TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels that are involved in many physiological processes. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal ...TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels that are involved in many physiological processes. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans, but their pathogenic mechanism remains elusive. Here, we report the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. Based on these structures and accompanying electrophysiological studies, we identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are also structurally and functionally conserved in TRPC6. We uncovered that the GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Furthermore, structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets reveal different conformations of the transmembrane domain, providing templates for further structure-based drug design targeting TRPC6-related diseases such as FSGS.
History
DepositionJan 18, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 17, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 5, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
A: Short transient receptor potential channel 6
B: Short transient receptor potential channel 6
C: Short transient receptor potential channel 6
D: Short transient receptor potential channel 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)441,17944
Polymers425,8134
Non-polymers15,36640
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area37980 Å2
ΔGint-347 kcal/mol
Surface area124560 Å2

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Short transient receptor potential channel 6 / TrpC6 / Transient receptor protein 6 / TRP-6


Mass: 106453.242 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPC6, TRP6 / Production host: Homo sapiens (human) / References: UniProt: Q9Y210

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Non-polymers , 6 types, 40 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C31H50O4
#5: Chemical
ChemComp-HOR / 4-[[(1R,2R)-2-[(3R)-3-azanylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-chloranyl-benzenecarbonitrile / SAR7334


Mass: 367.872 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H22ClN3O / Feature type: SUBJECT OF INVESTIGATION
#6: 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
#7: Chemical
ChemComp-98R / [(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate


Mass: 620.986 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C39H72O5

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Details

Has ligand of interestY

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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 6 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 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 82862 / Symmetry type: POINT

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