+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-10909 | |||||||||
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Title | Human TRPC5 in the presence of 50 uM Pico145 (HC-608) | |||||||||
Map data | ||||||||||
Sample |
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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 / detection of maltose stimulus / maltose binding / maltose transport complex / maltose transport / maltodextrin transmembrane transport / carbohydrate transmembrane transporter activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / carbohydrate transport / positive regulation of axon extension / calcium channel complex / regulation of cytosolic calcium ion concentration / positive regulation of neuron differentiation / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / positive regulation of peptidyl-threonine phosphorylation / calcium ion transmembrane transport / calcium channel activity / neuron differentiation / calcium ion transport / outer membrane-bounded periplasmic space / nervous system development / actin binding / ATPase binding / positive regulation of cytosolic calcium ion concentration / growth cone / neuron apoptotic process / periplasmic space / dendrite / neuronal cell body / DNA damage response / positive regulation of cell population proliferation / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Wright DJ / Johnson RM / Muench SP / Bon RS | |||||||||
Funding support | United Kingdom, 1 items
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Citation | Journal: Commun Biol / Year: 2020 Title: Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site. Authors: David J Wright / Katie J Simmons / Rachel M Johnson / David J Beech / Stephen P Muench / Robin S Bon / Abstract: TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational ...TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. Xanthine-based modulators include the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Here we report the structure of a small-molecule-bound TRPC1/4/5 channel-human TRPC5 in complex with the xanthine Pico145-to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_10909.map.gz | 59.9 MB | EMDB map data format | |
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Header (meta data) | emd-10909-v30.xml emd-10909.xml | 9.5 KB 9.5 KB | Display Display | EMDB header |
Images | emd_10909.png | 124.8 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-10909 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-10909 | HTTPS FTP |
-Related structure data
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_10909.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Homotetrameric TRPC5
Entire | Name: Homotetrameric TRPC5 |
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Components |
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-Supramolecule #1: Homotetrameric TRPC5
Supramolecule | Name: Homotetrameric TRPC5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 2 mg/mL | ||||||||||||
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Buffer | pH: 7.5 Component:
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Initial angle assignment | Type: NOT APPLICABLE |
Final angle assignment | Type: NOT APPLICABLE |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Software - details: 3.0.7 / Number images used: 158548 |