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- EMDB-30907: Structure of BTDM-bound human TRPC6 nanodisc at 2.9 angstrom in h... -

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Basic information

Entry
Database: EMDB / ID: EMD-30907
TitleStructure of BTDM-bound human TRPC6 nanodisc at 2.9 angstrom in high calcium state
Map datasharpened map
Sample
  • Complex: human transient receptor potential channel 6 tetramer
    • Protein or peptide: Short transient receptor potential channel 6
  • Ligand: ZINC ION
  • Ligand: [2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-[(3R,5S)-3,5-dimethylpiperidin-1-yl]methanone
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CALCIUM 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
KeywordsTRPC6 / TRPC / calcium / BTDM / FSGS / channel / MEMBRANE PROTEIN
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 / 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 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: 2.9 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-7dxf
  • Surface level: 0.8
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30907.png

Downloads & links

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Map

FileDownload / File: emd_30907.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.8 / Movie #1: 0.8
Minimum - Maximum-2.8149395 - 6.2912354
Average (Standard dev.)0.0058176704 (±0.19416931)
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-2.8156.2910.006

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Supplemental data

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Half map: half map A

Fileemd_30907_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_30907_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 6 tetramer

EntireName: human transient receptor potential channel 6 tetramer
Components
  • Complex: human transient receptor potential channel 6 tetramer
    • Protein or peptide: Short transient receptor potential channel 6
  • Ligand: ZINC ION
  • Ligand: [2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-[(3R,5S)-3,5-dimethylpiperidin-1-yl]methanone
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: CALCIUM 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 6 tetramer

SupramoleculeName: human transient receptor potential channel 6 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 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: 106.453242 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSQSPAFGPR RGSSPRGAAG AAARRNESQD YLLMDSELGE DGCPQAPLPC YGYYPCFRGS DNRLAHRRQT VLREKGRRLA NRGPAYMFS DRSTSLSIEE ERFLDAAEYG NIPVVRKMLE ECHSLNVNCV DYMGQNALQL AVANEHLEIT ELLLKKENLS R VGDALLLA ...String:
MSQSPAFGPR RGSSPRGAAG AAARRNESQD YLLMDSELGE DGCPQAPLPC YGYYPCFRGS DNRLAHRRQT VLREKGRRLA NRGPAYMFS DRSTSLSIEE ERFLDAAEYG NIPVVRKMLE ECHSLNVNCV DYMGQNALQL AVANEHLEIT ELLLKKENLS R VGDALLLA ISKGYVRIVE AILSHPAFAE GKRLATSPSQ SELQQDDFYA YDEDGTRFSH DVTPIILAAH CQEYEIVHTL LR KGARIER PHDYFCKCND CNQKQKHDSF SHSRSRINAY KGLASPAYLS LSSEDPVMTA LELSNELAVL ANIEKEFKND YKK LSMQCK DFVVGLLDLC RNTEEVEAIL NGDVETLQSG DHGRPNLSRL KLAIKYEVKK FVAHPNCQQQ LLSIWYENLS GLRQ QTMAV KFLVVLAVAI GLPFLALIYW FAPCSKMGKI MRGPFMKFVA HAASFTIFLG LLVMNAADRF EGTKLLPNET STDNA KQLF RMKTSCFSWM EMLIISWVIG MIWAECKEIW TQGPKEYLFE LWNMLDFGML AIFAASFIAR FMAFWHASKA QSIIDA NDT LKDLTKVTLG DNVKYYNLAR IKWDPSDPQI ISEGLYAIAV VLSFSRIAYI LPANESFGPL QISLGRTVKD IFKFMVI FI MVFVAFMIGM FNLYSYYIGA KQNEAFTTVE ESFKTLFWAI FGLSEVKSVV INYNHKFIEN IGYVLYGVYN VTMVIVLL N MLIAMINSSF QEIEDDADVE WKFARAKLWF SYFEEGRTLP VPFNLVPSPK SLFYLLLKLK KWISELFQGH KKGFQEDAE MNKINEEKKL GILGSHEDLS KLSLDKKQVG HNKQPSIRSS EDFHLNSFNN PPRQYQKIMK RLIKRYVLQA QIDKESDEVN EGELKEIKQ DISSLRYELL EEKSQNTEDL AELIRELGEK LSMEPNQEET NR

UniProtKB: Short transient receptor potential channel 6

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #3: [2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-[(3R,5S)-3,5-dim...

MacromoleculeName: [2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-[(3R,5S)-3,5-dimethylpiperidin-1-yl]methanone
type: ligand / ID: 3 / Number of copies: 4 / Formula: W99
Molecular weightTheoretical: 359.443 Da
Chemical component information

ChemComp-W99:
[2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-[(3R,5S)-3,5-dimethylpiperidin-1-yl]methanone

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Macromolecule #4: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 4 / Number of copies: 12 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 12 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #6: (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: 6 / 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 #7: [(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: 7 / 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:

6911

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95686
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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