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- EMDB-30575: Structure of human TRPC5 in complex with clemizole -

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Basic information

Entry
Database: EMDB / ID: EMD-30575
TitleStructure of human TRPC5 in complex with clemizole
Map dataSHARPENED MAP
Sample
  • Complex: human transient receptor potential channel 5 tetramer
    • Protein or peptide: Short transient receptor potential channel 5
  • Ligand: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: ZINC ION
  • Ligand: CALCIUM IONCalcium
  • Ligand: (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate
Function / homology
Function and homology information


regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / cation channel complex / inositol 1,4,5 trisphosphate binding / actinin binding / TRP channels / clathrin binding ...regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / Role of second messengers in netrin-1 signaling / store-operated calcium channel activity / cation channel complex / inositol 1,4,5 trisphosphate binding / actinin binding / TRP channels / clathrin binding / positive regulation of axon extension / calcium channel complex / regulation of cytosolic calcium ion concentration / positive regulation of neuron differentiation / positive regulation of peptidyl-threonine phosphorylation / calcium ion transmembrane transport / calcium channel activity / neuron differentiation / calcium ion transport / nervous system development / actin binding / ATPase binding / positive regulation of cytosolic calcium ion concentration / growth cone / neuron apoptotic process / dendrite / neuronal cell body / positive regulation of cell population proliferation / plasma membrane
Similarity search - Function
Transient receptor potential channel, canonical 5 / Transient receptor ion channel II / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeat / Ankyrin repeats (3 copies) / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential channel, canonical 5 / Transient receptor ion channel II / Transient receptor ion channel domain / Transient receptor ion channel II / Transient receptor potential channel, canonical / Ankyrin repeat / Ankyrin repeats (3 copies) / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Short transient receptor potential channel 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsChen L / Song K / Wei M / Guo W
Funding support China, 5 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
National Natural Science Foundation of China (NSFC) China
CitationJournal: Elife / Year: 2021
Title: Structural basis for human TRPC5 channel inhibition by two distinct inhibitors.
Authors: Kangcheng Song / Miao Wei / Wenjun Guo / Li Quan / Yunlu Kang / Jing-Xiang Wu / Lei Chen /
Abstract: TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. ...TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.
History
DepositionSep 24, 2020-
Header (metadata) releaseMar 31, 2021-
Map releaseMar 31, 2021-
UpdateOct 13, 2021-
Current statusOct 13, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.955
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.955
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7d4p
  • Surface level: 0.955
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30575.png

Downloads & links

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Map

FileDownload / File: emd_30575.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: 0.955 / Movie #1: 0.955
Minimum - Maximum-3.709709 - 6.0407476
Average (Standard dev.)0.009970403 (±0.19614697)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 292.60004 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-3.7106.0410.010

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Supplemental data

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Half map: half map A

Fileemd_30575_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_30575_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 5 tetramer

EntireName: human transient receptor potential channel 5 tetramer
Components
  • Complex: human transient receptor potential channel 5 tetramer
    • Protein or peptide: Short transient receptor potential channel 5
  • Ligand: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: ZINC ION
  • Ligand: CALCIUM IONCalcium
  • Ligand: (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate

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Supramolecule #1: human transient receptor potential channel 5 tetramer

SupramoleculeName: human transient receptor potential channel 5 tetramer / type: complex / 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 5

MacromoleculeName: Short transient receptor potential channel 5 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 88.848578 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAQLYYKKVN YSPYRDRIPL QIVRAETELS AEEKAFLNAV EKGDYATVKQ ALQEAEIYYN VNINCMDPLG RSALLIAIEN ENLEIMELL LNHSVYVGDA LLYAIRKEVV GAVELLLSYR RPSGEKQVPT LMMDTQFSEF TPDITPIMLA AHTNNYEIIK L LVQKRVTI ...String:
MAQLYYKKVN YSPYRDRIPL QIVRAETELS AEEKAFLNAV EKGDYATVKQ ALQEAEIYYN VNINCMDPLG RSALLIAIEN ENLEIMELL LNHSVYVGDA LLYAIRKEVV GAVELLLSYR RPSGEKQVPT LMMDTQFSEF TPDITPIMLA AHTNNYEIIK L LVQKRVTI PRPHQIRCNC VECVSSSEVD SLRHSRSRLN IYKALASPSL IALSSEDPIL TAFRLGWELK ELSKVENEFK AE YEELSQQ CKLFAKDLLD QARSSRELEI ILNHRDDHSE ELDPQKYHDL AKLKVAIKYH QKEFVAQPNC QQLLATLWYD GFP GWRRKH WVVKLLTCMT IGFLFPMLSI AYLISPRSNL GLFIKKPFIK FICHTASYLT FLFMLLLASQ HIVRTDLHVQ GPPP TVVEW MILPWVLGFI WGEIKEMWDG GFTEYIHDWW NLMDFAMNSL YLATISLKIV AYVKYNGSRP REEWEMWHPT LIAEA LFAI SNILSSLRLI SLFTANSHLG PLQISLGRML LDILKFLFIY CLVLLAFANG LNQLYFYYET RAIDEPNNCK GIRCEK QNN AFSTLFETLQ SLFWSVFGLL NLYVTNVKAR HEFTEFVGAT MFGTYNVISL VVLLNMLIAM MNNSYQLIAD HADIEWK FA RTKLWMSYFD EGGTLPPPFN IIPSPKSFLY LGNWFNNTFC PKRDPDGRRR RRNLRSFTER NADSLIQNQH YQEVIRNL V KRYVAAMIRN SKTHEGLTEE NFKELKQDIS SFRYEVLDLL GNR

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Macromolecule #2: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole

MacromoleculeName: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole
type: ligand / ID: 2 / Number of copies: 4 / Formula: GX0
Molecular weightTheoretical: 325.835 Da
Chemical component information

ChemComp-GX0:
1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole / antagonist*YM / Clemizole

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Macromolecule #3: PHOSPHATIDYLETHANOLAMINE

MacromoleculeName: PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 3 / Number of copies: 4 / Formula: PTY
Molecular weightTheoretical: 734.039 Da
Chemical component information

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

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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 / POPC

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 4 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #8: (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate

MacromoleculeName: (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate
type: ligand / ID: 8 / Number of copies: 4 / Formula: YZY
Molecular weightTheoretical: 594.949 Da
Chemical component information

ChemComp-YZY:
(2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-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
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 QUANTUM (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

6856

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. V1) / Number images used: 90357

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