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- PDB-6ysn: Human TRPC5 in complex with Pico145 (HC-608) -

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Basic information

Entry
Database: PDB / ID: 6ysn
TitleHuman TRPC5 in complex with Pico145 (HC-608)
ComponentsMaltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
KeywordsMEMBRANE PROTEIN / Ion channel / small molecule / inhibitor / tetramer
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
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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein ...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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / 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
Chem-PJQ / Maltose/maltodextrin-binding periplasmic protein / Short transient receptor potential channel 5
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsWright, D.J. / Johnson, R.M. / Muench, S.P. / Bon, R.S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/P020208/1 United Kingdom
CitationJournal: 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
DepositionApr 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 9, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
B: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
C: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
D: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)525,1408
Polymers523,0404
Non-polymers2,1004
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area34760 Å2
ΔGint-230 kcal/mol
Surface area115880 Å2
MethodPISA

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Components

#1: Protein
Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / TrpC5 / Transient receptor ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / TrpC5 / Transient receptor protein 5 / hTRP5


Mass: 130760.031 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (strain K12) (bacteria), (gene. exp.) Homo sapiens (human)
Strain: K12 / Gene: malE, b4034, JW3994, TRPC5, TRP5 / Production host: Homo sapiens (human) / References: UniProt: P0AEX9, UniProt: Q9UL62
#2: Chemical
ChemComp-PJQ / 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(trifluoromethyloxy)phenoxy]purine-2,6-dione


Mass: 524.877 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H20ClF3N4O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Homotetrameric TRPC5 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli (strain K12) (bacteria)83333
31Homo sapiens (human)9606
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium ChlorideNaClSodium chloride1
230 mMHEPES1
31 mMDTT1
440 mMMaltose1
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Final sample in PMAL-C8 amphipol
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 130000 X / Nominal defocus max: -3 nm / Nominal defocus min: -1 nm / C2 aperture diameter: 70 µm
Image recordingAverage exposure time: 10 sec. / Electron dose: 75 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Image scansMovie frames/image: 40

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM softwareName: RELION / Category: 3D reconstruction / Details: 3.0.7
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 158111 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00420992
ELECTRON MICROSCOPYf_angle_d0.5528442
ELECTRON MICROSCOPYf_dihedral_angle_d8.35512464
ELECTRON MICROSCOPYf_chiral_restr0.043181
ELECTRON MICROSCOPYf_plane_restr0.0053521

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