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- EMDB-30906: Structure of TRPC3 gain of function mutation R803C at 3.2 angstro... -

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Basic information

Entry
Database: EMDB / ID: EMD-30906
TitleStructure of TRPC3 gain of function mutation R803C at 3.2 angstrom in 1340nM free calcium state
Map dataSHARPENED MAP
Sample
  • Complex: human transient receptor potential channel 3 tetramer
    • Protein or peptide: Short transient receptor potential channel 3
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: ZINC ION
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: [(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate
KeywordsTRPC3 / TRPC / calcium / gain of function / channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of cardiac muscle hypertrophy in response to stress / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / cation channel complex / inositol 1,4,5 trisphosphate binding / calcium-activated cation channel activity / TRP channels / positive regulation of calcium ion transport into cytosol ...positive regulation of cardiac muscle hypertrophy in response to stress / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / cation channel complex / inositol 1,4,5 trisphosphate binding / calcium-activated cation channel activity / TRP channels / positive regulation of calcium ion transport into cytosol / response to ATP / phototransduction / single fertilization / MECP2 regulates neuronal receptors and channels / regulation of cytosolic calcium ion concentration / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / calcium ion transport / metal ion binding / plasma membrane
Similarity search - Function
Transient receptor potential channel, canonical 3 / 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 region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential channel, canonical 3 / 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 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 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsChen L / Guo W
Funding support China, 4 items
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, 2021-
Header (metadata) releaseFeb 2, 2022-
Map releaseFeb 2, 2022-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.8
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.8
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dxe
  • Surface level: 0.8
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30906.png

Downloads & links

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Map

FileDownload / File: emd_30906.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSHARPENED MAP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 280 pix.
= 292.6 Å		1.05 Å/pix.
x 280 pix.
= 292.6 Å		1.05 Å/pix.
x 280 pix.
= 292.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.8 / Movie #1: 0.8
Minimum - Maximum-1.7131269 - 3.611785
Average (Standard dev.)0.015252946 (±0.13116556)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 292.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0451.0451.045
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z292.600292.600292.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-1.7133.6120.015

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Supplemental data

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Half map: half map A

Fileemd_30906_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_30906_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human transient receptor potential channel 3 tetramer

EntireName: human transient receptor potential channel 3 tetramer
Components
  • Complex: human transient receptor potential channel 3 tetramer
    • Protein or peptide: Short transient receptor potential channel 3
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: ZINC ION
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: [(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate

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Supramolecule #1: human transient receptor potential channel 3 tetramer

SupramoleculeName: human transient receptor potential channel 3 tetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Short transient receptor potential channel 3

MacromoleculeName: Short transient receptor potential channel 3 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 96.118227 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MREKGRRQAV RGPAFMFNDR GTSLTAEEER FLDAAEYGNI PVVRKMLEES KTLNVNCVDY MGQNALQLAV GNEHLEVTEL LLKKENLAR IGDALLLAIS KGYVRIVEAI LNHPGFAASK RLTLSPCEQE LQDDDFYAYD EDGTRFSPDI TPIILAAHCQ K YEVVHMLL ...String:
MREKGRRQAV RGPAFMFNDR GTSLTAEEER FLDAAEYGNI PVVRKMLEES KTLNVNCVDY MGQNALQLAV GNEHLEVTEL LLKKENLAR IGDALLLAIS KGYVRIVEAI LNHPGFAASK RLTLSPCEQE LQDDDFYAYD EDGTRFSPDI TPIILAAHCQ K YEVVHMLL MKGARIERPH DYFCKCGDCM EKQRHDSFSH SRSRINAYKG LASPAYLSLS SEDPVLTALE LSNELAKLAN IE KEFKNDY RKLSMQCKDF VVGVLDLCRD SEEVEAILNG DLESAEPLEV HRHKASLSRV KLAIKYEVKK FVAHPNCQQQ LLT IWYENL SGLREQTIAI KCLVVLVVAL GLPFLAIGYW IAPCSRLGKI LRSPFMKFVA HAASFIIFLG LLVFNASDRF EGIT TLPNI TVTDYPKQIF RVKTTQFTWT EMLIMVWVLG MMWSECKELW LEGPREYILQ LWNVLDFGML SIFIAAFTAR FLAFL QATK AQQYVDSYVQ ESDLSEVTLP PEIQYFTYAR DKWLPSDPQI ISEGLYAIAV VLSFSRIAYI LPANESFGPL QISLGR TVK DIFKFMVLFI MVFFAFMIGM FILYSYYLGA KVNAAFTTVE ESFKTLFWSI FGLSEVTSVV LKYDHKFIEN IGYVLYG IY NVTMVVVLLN MLIAMINSSY QEIEDDSDVE WKFARSKLWL SYFDDGKTLP PPFSLVPSPK SFVYFIMRIV NFPKCRRR R LQKDIEMGMG NSKSRLNLFT QSNSRVFESH SFNSILNQPT RYQQIMKRLI KRYVLKAQVD KENDEVNEGE LKEIKQDIS SLRYELLEDK SQATEELAIL IHKLSEKLNP SMLRCE

UniProtKB: Short transient receptor potential channel 3

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 8 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 4 / Number of copies: 4 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #5: [(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate

MacromoleculeName: [(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate
type: ligand / ID: 5 / Number of copies: 4 / Formula: 98R
Molecular weightTheoretical: 620.986 Da
Chemical component information

ChemComp-98R:
[(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / 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

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

7620

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 53304
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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