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- PDB-6uza: Cryo-EM structure of human TRPC6 in complex with antagonist AM-1473 -

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Basic information

Entry
Database: PDB / ID: 6uza
TitleCryo-EM structure of human TRPC6 in complex with antagonist AM-1473
ComponentsShort transient receptor potential channel 6
KeywordsTRANSPORT PROTEIN / TRP channel / Antagonist
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-R0G / Chem-S9Y / Chem-SBJ / CHOLESTEROL HEMISUCCINATE / Short transient receptor potential channel 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsBai, Y. / Yu, X. / Huang, X. / Chen, H.
CitationJournal: Elife / Year: 2020
Title: Structural basis for pharmacological modulation of the TRPC6 channel.
Authors: Yonghong Bai / Xinchao Yu / Hao Chen / Daniel Horne / Ryan White / Xiaosu Wu / Paul Lee / Yan Gu / Sudipa Ghimire-Rijal / Daniel C-H Lin / Xin Huang /
Abstract: Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic ...Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.
History
DepositionNov 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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 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)398,05624
Polymers388,8114
Non-polymers9,24520
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 97202.867 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
#2: Chemical
ChemComp-R0G / 4-({(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl}oxy)benzonitrile


Mass: 333.427 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H23N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-S9Y / 2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium


Mass: 396.479 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H39NO6P
#4: Chemical
ChemComp-SBJ / [(2~{S})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-octanoyloxy-propan-2-yl] octadecanoate


Mass: 607.800 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H62NO8P
#5: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C31H50O4
Has ligand of interestY
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: TRPC6 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
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 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.14_3260refinement
PHENIX1.14_3260refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90014 / Symmetry type: POINT
RefinementStereochemistry target values: CDL v1.2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00523828
ELECTRON MICROSCOPYf_angle_d0.772932312
ELECTRON MICROSCOPYf_chiral_restr0.04713684
ELECTRON MICROSCOPYf_plane_restr0.00683956
ELECTRON MICROSCOPYf_dihedral_angle_d10.0613992

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