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- EMDB-20954: Cryo-EM structure of human TRPC6 in complex with antagonist AM-1473 -

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Basic information

Entry
Database: EMDB / ID: EMD-20954
TitleCryo-EM structure of human TRPC6 in complex with antagonist AM-1473
Map data
Sample
  • Organelle or cellular component: TRPC6
    • Protein or peptide: Short transient receptor potential channel 6
  • Ligand: 4-({(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl}oxy)benzonitrile
  • Ligand: 2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium
  • Ligand: [(2~{S})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-octanoyloxy-propan-2-yl] octadecanoate
  • Ligand: CHOLESTEROL HEMISUCCINATE
Function / homology
Function and homology information


positive regulation of ion transmembrane transporter activity / slit diaphragm / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / Elevation of cytosolic Ca2+ levels / Effects of PIP2 hydrolysis / cation channel complex / inositol 1,4,5 trisphosphate binding / positive regulation of calcium ion transport / TRP channels ...positive regulation of ion transmembrane transporter activity / slit diaphragm / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / Elevation of cytosolic Ca2+ levels / Effects of PIP2 hydrolysis / cation channel complex / inositol 1,4,5 trisphosphate binding / positive regulation of calcium ion transport / TRP channels / single fertilization / monoatomic cation transport / 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 II / Transient receptor ion channel domain / 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 II / Transient receptor ion channel domain / 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
Short transient receptor potential channel 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle 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, 2019-
Header (metadata) releaseMar 18, 2020-
Map releaseMar 18, 2020-
UpdateMar 18, 2020-
Current statusMar 18, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 5.5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 5.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6uza
  • Surface level: 5.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20954.png

Downloads & links

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Map

FileDownload / File: emd_20954.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.832 Å
Density
Contour LevelBy AUTHOR: 5.5 / Movie #1: 5.5
Minimum - Maximum-26.106977 - 38.795166
Average (Standard dev.)0.0000000000 (±1)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 332.80002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8320.8320.832
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z332.800332.800332.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-26.10738.7950.000

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Supplemental data

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Sample components

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Entire : TRPC6

EntireName: TRPC6
Components
  • Organelle or cellular component: TRPC6
    • Protein or peptide: Short transient receptor potential channel 6
  • Ligand: 4-({(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl}oxy)benzonitrile
  • Ligand: 2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium
  • Ligand: [(2~{S})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-octanoyloxy-propan-2-yl] octadecanoate
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: TRPC6

SupramoleculeName: TRPC6 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Short transient receptor potential channel 6

MacromoleculeName: Short transient receptor potential channel 6 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 97.202867 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AYMFSDRSTS LSIEEERFLD AAEYGNIPVV RKMLEECHSL NVNCVDYMGQ NALQLAVANE HLEITELLLK KENLSRVGDA LLLAISKGY VRIVEAILSH PAFAEGKRLA TSPSQSELQQ DDFYAYDEDG TRFSHDVTPI ILAAHCQEYE IVHTLLRKGA R IERPHDYF ...String:
AYMFSDRSTS LSIEEERFLD AAEYGNIPVV RKMLEECHSL NVNCVDYMGQ NALQLAVANE HLEITELLLK KENLSRVGDA LLLAISKGY VRIVEAILSH PAFAEGKRLA TSPSQSELQQ DDFYAYDEDG TRFSHDVTPI ILAAHCQEYE IVHTLLRKGA R IERPHDYF CKCNDCNQKQ KHDSFSHSRS RINAYKGLAS PAYLSLSSED PVMTALELSN ELAVLANIEK EFKNDYKKLS MQ CKDFVVG LLDLCRNTEE VEAILNGDVE TLQSGDHGRP NLSRLKLAIK YEVKKFVAHP NCQQQLLSIW YENLSGLRQQ TMA VKFLVV LAVAIGLPFL ALIYWFAPCS KMGKIMRGPF MKFVAHAASF TIFLGLLVMN AADRFEGTKL LPNETSTDNA KQLF RMKTS CFSWMEMLII SWVIGMIWAE CKEIWTQGPK EYLFELWNML DFGMLAIFAA SFIARFMAFW HASKAQSIID ANDTL KDLT KVTLGDNVKY YNLARIKWDP SDPQIISEGL YAIAVVLSFS RIAYILPANE SFGPLQISLG RTVKDIFKFM VIFIMV FVA FMIGMFNLYS YYIGAKQNEA FTTVEESFKT LFWAIFGLSE VKSVVINYNH KFIENIGYVL YGVYNVTMVI VLLNMLI AM INSSFQEIED DADVEWKFAR AKLWFSYFEE GRTLPVPFNL VPSPKSLFYL LLKLKKWISE LFQGHKKGFQ EDAEMNKI N EEKKLGILGS HEDLSKLSLD KKQVGHNKQP SIRSSEDFHL NSFNNPPRQY QKIMKRLIKR YVLQAQIDKE SDEVNEGEL KEIKQDISSL RYELLEEKSQ NTEDLAELIR ELGEKLSMEP NQEETNR

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Macromolecule #2: 4-({(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1...

MacromoleculeName: 4-({(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl}oxy)benzonitrile
type: ligand / ID: 2 / Number of copies: 4 / Formula: R0G
Molecular weightTheoretical: 333.427 Da
Chemical component information

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

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Macromolecule #3: 2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-tr...

MacromoleculeName: 2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium
type: ligand / ID: 3 / Number of copies: 4 / Formula: S9Y
Molecular weightTheoretical: 396.479 Da
Chemical component information

ChemComp-S9Y:
2-[[(2~{S})-2-decanoyloxypropoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium

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Macromolecule #4: [(2~{S})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-octanoyloxy-...

MacromoleculeName: [(2~{S})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-octanoyloxy-propan-2-yl] octadecanoate
type: ligand / ID: 4 / Number of copies: 4 / Formula: SBJ
Molecular weightTheoretical: 607.8 Da
Chemical component information

ChemComp-SBJ:
[(2~{S})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-octanoyloxy-propan-2-yl] octadecanoate

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 8 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 90014
FSC plot (resolution estimation)

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