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- EMDB-10903: Human TRPC5 in complex with Pico145 (HC-608) -

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Basic information

Entry
Database: EMDB / ID: EMD-10903
TitleHuman TRPC5 in complex with Pico145 (HC-608)
Map data
Sample
  • Complex: Homotetrameric TRPC5
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
  • Ligand: 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(trifluoromethyloxy)phenoxy]purine-2,6-dione
KeywordsIon channel / small molecule / inhibitor / tetramer / MEMBRANE PROTEIN
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 / inositol 1,4,5 trisphosphate binding / cation channel complex / 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 / inositol 1,4,5 trisphosphate binding / cation channel complex / actinin binding / TRP channels / clathrin binding / detection of maltose stimulus / maltose transport complex / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / regulation of cytosolic calcium ion concentration / positive regulation of axon extension / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / calcium channel complex / positive regulation of neuron differentiation / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / calcium ion transmembrane transport / calcium channel activity / neuron differentiation / calcium ion transport / nervous system development / presynapse / actin binding / outer membrane-bounded periplasmic space / ATPase binding / growth cone / positive regulation of cytosolic calcium ion concentration / neuron apoptotic process / periplasmic space / neuronal cell body / positive regulation of cell population proliferation / dendrite / DNA damage response / membrane / plasma membrane
Similarity search - Function
Transient receptor potential channel, canonical 5 / Transient receptor ion channel domain / Transient receptor ion channel II / 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 domain / Transient receptor ion channel II / 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
Maltose/maltodextrin-binding periplasmic protein / Short transient receptor potential channel 5
Similarity search - Component
Biological speciesEscherichia coli (strain K12) (bacteria) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsWright DJ / Johnson RM
Funding support United Kingdom, 1 items
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, 2020-
Header (metadata) releaseDec 2, 2020-
Map releaseDec 2, 2020-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6ysn
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_10903.png

Downloads & links

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Map

FileDownload / File: emd_10903.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.045 / Movie #1: 0.045
Minimum - Maximum-0.21271043 - 0.33187717
Average (Standard dev.)-0.000048001453 (±0.009552593)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.92 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z273.920273.920273.920
α/β/γ90.00090.00090.000
start NX/NY/NZ79740
NX/NY/NZ93103213
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.2130.332-0.000

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Supplemental data

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Sample components

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Entire : Homotetrameric TRPC5

EntireName: Homotetrameric TRPC5
Components
  • Complex: Homotetrameric TRPC5
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
  • Ligand: 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(trifluoromethyloxy)phenoxy]purine-2,6-dione

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Supramolecule #1: Homotetrameric TRPC5

SupramoleculeName: Homotetrameric TRPC5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Escherichia coli (strain K12) (bacteria)

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Macromolecule #1: Maltose/maltodextrin-binding periplasmic protein,Short transient ...

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130.760031 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY ...String:
MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SK VNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAA TMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGLE VRQTVDEALK DAQTSSGLGV LFQGPMAQLY YKKVNYSPYR DRIP LQIVR AETELSAEEK AFLNAVEKGD YATVKQALQE AEIYYNVNIN CMDPLGRSAL LIAIENENLE IMELLLNHSV YVGDA LLYA IRKEVVGAVE LLLSYRRPSG EKQVPTLMMD TQFSEFTPDI TPIMLAAHTN NYEIIKLLVQ KRVTIPRPHQ IRCNCV ECV SSSEVDSLRH SRSRLNIYKA LASPSLIALS SEDPILTAFR LGWELKELSK VENEFKAEYE ELSQQCKLFA KDLLDQA RS SRELEIILNH RDDHSEELDP QKYHDLAKLK VAIKYHQKEF VAQPNCQQLL ATLWYDGFPG WRRKHWVVKL LTCMTIGF L FPMLSIAYLI SPRSNLGLFI KKPFIKFICH TASYLTFLFM LLLASQHIVR TDLHVQGPPP TVVEWMILPW VLGFIWGEI KEMWDGGFTE YIHDWWNLMD FAMNSLYLAT ISLKIMAYVK YNGSRPREEW EMWHPTLIAE ALFAISNILS SLRLISLFTA NSHLGPLQI SLGRMLLDIL KFLFIYCLVL LAFANGLNQL YFYYETRAID EPNNCKGIRC EKQNNAFSTL FETLQSLFWS V FGLLNLYV TNVKARHEFT EFVGATMFGT YNVISLVVLL NMLIAMMNNS YQLIADHADI EWKFARTKLW MSYFDEGGTL PP PFNIIPS PKSFLYLGNW FNNTFCPKRD PDGRRRRRNL RSFTERNADS LIQNQHYQEV IRNLVKRYVA AMIRNSKTHE GLT EENFKE LKQDISSFRY EVLDLLGNRK

UniProtKB: Maltose/maltodextrin-binding periplasmic protein, Short transient receptor potential channel 5

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Macromolecule #2: 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(tr...

MacromoleculeName: 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(trifluoromethyloxy)phenoxy]purine-2,6-dione
type: ligand / ID: 2 / Number of copies: 4 / Formula: PJQ
Molecular weightTheoretical: 524.877 Da
Chemical component information

ChemComp-PJQ:
7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(trifluoromethyloxy)phenoxy]purine-2,6-dione

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClSodium Chloride
30.0 mMHEPES
1.0 mMDTT
40.0 mMMaltose
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE
DetailsFinal sample in PMAL-C8 amphipol

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average exposure time: 10.0 sec. / Average electron dose: 75.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: -0.003 µm / Nominal defocus min: -0.001 µm / Nominal magnification: 130000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6aei

Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Software - details: 3.0.7 / Number images used: 158111
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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