[English] 日本語
Yorodumi
- EMDB-20954: Cryo-EM structure of human TRPC6 in complex with antagonist AM-1473 -

+
Open data


ID or keywords:

Loading...

-
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
KeywordsTRP channel / Antagonist / TRANSPORT PROTEIN
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 / regulation of cytosolic calcium ion concentration / monoatomic cation channel activity / calcium channel activity / calcium ion transmembrane transport / 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
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
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-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

-
Structure visualization

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

emd_20954.png

Downloads & links

-
Map

FileDownload / File: emd_20954.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 400 pix.
= 332.8 Å		0.83 Å/pix.
x 400 pix.
= 332.8 Å		0.83 Å/pix.
x 400 pix.
= 332.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.5 / Movie #1: 5.5
Minimum - Maximum-26.106977000000001 - 38.795166000000002
Average (Standard dev.)0.000000000002343 (±1.0)
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

-
Supplemental data

-
Sample components

-
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

-
Supramolecule #1: TRPC6

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

-
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

UniProtKB: Short transient receptor potential channel 6

-
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

-
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

-
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

-
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

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 8
GridDetails: unspecified
VitrificationCryogen name: ETHANE

-
Electron microscopy

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

+
Image processing

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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more