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- EMDB-20953: Cryo-EM structure of human TRPC6 in complex with agonist AM-0883 -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-20953 | |||||||||
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Title | Cryo-EM structure of human TRPC6 in complex with agonist AM-0883 | |||||||||
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Function / homology | ![]() 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 | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.84 Å | |||||||||
![]() | Bai Y / Yu X / Huang X / Chen H | |||||||||
![]() | ![]() 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 |
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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 | ![]() | 64.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 10.8 KB 10.8 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.3 KB | Display | ![]() |
Images | ![]() | 182 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6uz8MC ![]() 6uzaC 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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Voxel size | X=Y=Z: 1.248 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : TRPC6
Entire | Name: TRPC6 |
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Components |
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-Supramolecule #1: TRPC6
Supramolecule | Name: TRPC6 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Short transient receptor potential channel 6
Macromolecule | Name: Short transient receptor potential channel 6 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 97.192781 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 YTTQAQIDKE SDEVNEGEL KEIKQDISSL RYELLEEKSQ NTEDLAELIR ELGEKLSMEP NQEETNR |
-Macromolecule #2: 2-[[(2~{S})-2-decanoyloxy-3-dodecanoyloxy-propoxy]-oxidanyl-phosp...
Macromolecule | Name: 2-[[(2~{S})-2-decanoyloxy-3-dodecanoyloxy-propoxy]-oxidanyl-phosphoryl]oxyethyl-trimethyl-azanium type: ligand / ID: 2 / Number of copies: 4 / Formula: SBM |
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Molecular weight | Theoretical: 594.781 Da |
Chemical component information | ![]() ChemComp-SBM: |
-Macromolecule #3: CHOLESTEROL HEMISUCCINATE
Macromolecule | Name: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 8 / Formula: Y01 |
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Molecular weight | Theoretical: 486.726 Da |
Chemical component information | ![]() ChemComp-Y01: |
-Macromolecule #4: (5-chloro-1'H-spiro[indole-3,4'-piperidin]-1'-yl)[(2R)-2,3-dihydr...
Macromolecule | Name: (5-chloro-1'H-spiro[indole-3,4'-piperidin]-1'-yl)[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]methanone type: ligand / ID: 4 / Number of copies: 4 / Formula: R0D |
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Molecular weight | Theoretical: 382.84 Da |
Chemical component information | ![]() ChemComp-R0D: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |