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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-30575 | ||||||||||||||||||
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Title | Structure of human TRPC5 in complex with clemizole | ||||||||||||||||||
![]() | SHARPENED MAP | ||||||||||||||||||
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Function / homology | ![]() regulation of membrane hyperpolarization / phosphatidylserine exposure on apoptotic cell surface / negative regulation of dendrite morphogenesis / Role of second messengers in netrin-1 signaling / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||||||||
Biological species | ![]() ![]() | ||||||||||||||||||
Method | ![]() ![]() | ||||||||||||||||||
![]() | Chen L / Song K / Wei M / Guo W | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 78.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.9 KB 17.9 KB | Display Display | ![]() |
Images | ![]() | 82.7 KB | ||
Others | ![]() ![]() | 77.2 MB 77.1 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7d4pMC ![]() 7d4qC ![]() 7e4tC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | SHARPENED MAP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.045 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Half map: half map A
File | emd_30575_half_map_1.map | ||||||||||||
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Annotation | half map A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map B
File | emd_30575_half_map_2.map | ||||||||||||
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Annotation | half map B | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : human transient receptor potential channel 5 tetramer
Entire | Name: human transient receptor potential channel 5 tetramer |
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Components |
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-Supramolecule #1: human transient receptor potential channel 5 tetramer
Supramolecule | Name: human transient receptor potential channel 5 tetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: Short transient receptor potential channel 5
Macromolecule | Name: Short transient receptor potential channel 5 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 88.848578 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #2: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole
Macromolecule | Name: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole type: ligand / ID: 2 / Number of copies: 4 / Formula: GX0 |
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Molecular weight | Theoretical: 325.835 Da |
Chemical component information | ![]() ChemComp-GX0: |
-Macromolecule #3: PHOSPHATIDYLETHANOLAMINE
Macromolecule | Name: PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 3 / Number of copies: 4 / Formula: PTY |
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Molecular weight | Theoretical: 734.039 Da |
Chemical component information | ![]() ChemComp-PTY: |
-Macromolecule #4: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...
Macromolecule | Name: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate type: ligand / ID: 4 / Number of copies: 4 / Formula: POV |
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Molecular weight | Theoretical: 760.076 Da |
Chemical component information | ![]() ChemComp-POV: |
-Macromolecule #5: CHOLESTEROL HEMISUCCINATE
Macromolecule | Name: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 4 / Formula: Y01 |
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Molecular weight | Theoretical: 486.726 Da |
Chemical component information | ![]() ChemComp-Y01: |
-Macromolecule #6: ZINC ION
Macromolecule | Name: ZINC ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: ZN |
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Molecular weight | Theoretical: 65.409 Da |
-Macromolecule #7: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 4 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #8: (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate
Macromolecule | Name: (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate type: ligand / ID: 8 / Number of copies: 4 / Formula: YZY |
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Molecular weight | Theoretical: 594.949 Da |
Chemical component information | ![]() ChemComp-YZY: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film 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 model | Type of model: EMDB MAP EMDB ID: |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Applied symmetry - Point group: C4 (4 fold cyclic![]() |