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Yorodumi- PDB-7dxe: Structure of TRPC3 gain of function mutation R803C at 3.2 angstro... -
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-Basic information
Entry | Database: PDB / ID: 7dxe | |||||||||||||||
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Title | Structure of TRPC3 gain of function mutation R803C at 3.2 angstrom in 1340nM free calcium state | |||||||||||||||
Components | Short transient receptor potential channel 3 | |||||||||||||||
Keywords | MEMBRANE PROTEIN / TRPC3 / TRPC / calcium / gain of function / channel | |||||||||||||||
Function / homology | Chem-98R / Chem-POV / CHOLESTEROL HEMISUCCINATE / : Function and homology information | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||||||||
Authors | Chen, L. / Guo, W. | |||||||||||||||
Funding support | China, 4items
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Citation | Journal: 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 |
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-Structure visualization
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
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PDBx/mmCIF format | 7dxe.cif.gz | 557.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7dxe.ent.gz | 450.7 KB | Display | PDB format |
PDBx/mmJSON format | 7dxe.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7dxe_validation.pdf.gz | 2 MB | Display | wwPDB validaton report |
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Full document | 7dxe_full_validation.pdf.gz | 2.1 MB | Display | |
Data in XML | 7dxe_validation.xml.gz | 88 KB | Display | |
Data in CIF | 7dxe_validation.cif.gz | 122.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/dx/7dxe ftp://data.pdbj.org/pub/pdb/validation_reports/dx/7dxe | HTTPS FTP |
-Related structure data
Related structure data | 30906MC 7dxbC 7dxcC 7dxdC 7dxfC 7dxgC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 96118.227 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TRPC3, TRP3 / Production host: Homo sapiens (human) / References: UniProt: Q13507 #2: Chemical | ChemComp-Y01 / #3: Chemical | ChemComp-ZN / #4: Chemical | ChemComp-POV / ( #5: Chemical | ChemComp-98R / [( Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: human transient receptor potential channel 3 tetramer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 53304 / Symmetry type: POINT |