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- EMDB-54187: Human TRPC5 in complex with (-) englerin A, full occupancy, state... -

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Basic information

Entry
Database: EMDB / ID: EMD-54187
TitleHuman TRPC5 in complex with (-) englerin A, full occupancy, state 1, on 290 nm gold foil holes (HexAuFoil)
Map data
Sample
  • Cell: TRPC5 in presence of pluronic acid and (-)-englerin A
    • Protein or peptide: Short transient receptor potential channel 5
  • Ligand: CALCIUM ION
  • Ligand: ZINC ION
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: (-)-englerin A
KeywordsTRPC5 / (-) englerin A / agonist / 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 / clathrin binding / TRP channels ...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 / clathrin binding / TRP channels / regulation of cytosolic calcium ion concentration / positive regulation of axon extension / positive regulation of neuron differentiation / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / neuron differentiation / calcium ion transport / nervous system development / ATPase binding / growth cone / presynapse / positive regulation of cytosolic calcium ion concentration / actin binding / neuron apoptotic process / neuronal cell body / positive regulation of cell population proliferation / dendrite / metal ion binding / 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 / Ankyrin repeat / Ankyrin repeats (3 copies) / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...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 / 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
Short transient receptor potential channel 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsPorav AS / Bon RS / Muench S
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/P020208/1; BB/Z514925/1 United Kingdom
CitationJournal: Nat Commun / Year: 2026
Title: (-)-Englerin A binding to human TRPC5 exposes an aromatic interaction network in channel activation.
Authors: Sebastian A Porav / Alexandra Ptakova / Claudia C Bauer / Kasia L R Hammond / David J Beech / Viktorie Vlachova / Stephen P Muench / Robin S Bon /
Abstract: TRPC4/5 cation channels are polymodal cellular sensors and emerging drug targets in various human pathologies. The plant natural product (-)-englerin A (EA) is a potent, selective TRPC4/5 agonist ...TRPC4/5 cation channels are polymodal cellular sensors and emerging drug targets in various human pathologies. The plant natural product (-)-englerin A (EA) is a potent, selective TRPC4/5 agonist that has transformed TRPC4/5 research. However, the structural basis of EA-mediated TRPC4/5 activation has remained elusive, limiting our ability to understand and exploit EA's pharmacology. Here, we present nine high-resolution cryo-EM structures of human TRPC5, representing different states and ligand occupancies, which show that EA occupies a conserved lipid binding site between channel subunits. Conformational changes of residues surrounding this binding site - most notably in the aromatic interaction network around Phe520 - result in rearrangement of the pore helices into a pre-open state. Our structural models are consistent with the effects of mutagenesis on EA's potency, efficacy and activation kinetics, and allow us to rationalise competitive inhibition by other TRPC4/5 modulators as well as EA's selectivity profile within the TRPC family. Our structural insights into the mode-of-action of a widely used TRPC4/5 agonist will underpin fundamental TRPC4/5 research and ongoing drug discovery programmes.
History
DepositionJun 27, 2025-
Header (metadata) releaseMay 13, 2026-
Map releaseMay 13, 2026-
UpdateMay 13, 2026-
Current statusMay 13, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54187.png

Downloads & links

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Map

FileDownload / File: emd_54187.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.92 Å/pix.
x 360 pix.
= 331.2 Å		0.92 Å/pix.
x 360 pix.
= 331.2 Å		0.92 Å/pix.
x 360 pix.
= 331.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.7499891 - 1.6426467
Average (Standard dev.)0.000004378197 (±0.03023051)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 331.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_54187_msk_1.map
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Mask #2

Fileemd_54187_msk_2.map
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Additional map: Raw, unsharpened map

Fileemd_54187_additional_1.map
AnnotationRaw, unsharpened map
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Half map: #1

Fileemd_54187_half_map_1.map
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Half map: #2

Fileemd_54187_half_map_2.map
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Sample components

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Entire : TRPC5 in presence of pluronic acid and (-)-englerin A

EntireName: TRPC5 in presence of pluronic acid and (-)-englerin A
Components
  • Cell: TRPC5 in presence of pluronic acid and (-)-englerin A
    • Protein or peptide: Short transient receptor potential channel 5
  • Ligand: CALCIUM ION
  • Ligand: ZINC ION
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: (-)-englerin A

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Supramolecule #1: TRPC5 in presence of pluronic acid and (-)-englerin A

SupramoleculeName: TRPC5 in presence of pluronic acid and (-)-englerin A / type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Short transient receptor potential channel 5

MacromoleculeName: 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: 89.00982 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAQLYYKKVN YSPYRDRIPL QIVRAETELS AEEKAFLNAV EKGDYATVKQ ALQEAEIYYN VNINCMDPLG RSALLIAIEN ENLEIMELL LNHSVYVGDA LLYAIRKEVV GAVELLLSYR RPSGEKQVPT LMMDTQFSEF TPDITPIMLA AHTNNYEIIK L LVQKRVTI ...String:
MAQLYYKKVN YSPYRDRIPL QIVRAETELS AEEKAFLNAV EKGDYATVKQ ALQEAEIYYN VNINCMDPLG RSALLIAIEN ENLEIMELL LNHSVYVGDA LLYAIRKEVV GAVELLLSYR RPSGEKQVPT LMMDTQFSEF TPDITPIMLA AHTNNYEIIK L LVQKRVTI PRPHQIRCNC VECVSSSEVD SLRHSRSRLN IYKALASPSL IALSSEDPIL TAFRLGWELK ELSKVENEFK AE YEELSQQ CKLFAKDLLD QARSSRELEI ILNHRDDHSE ELDPQKYHDL AKLKVAIKYH QKEFVAQPNC QQLLATLWYD GFP GWRRKH WVVKLLTCMT IGFLFPMLSI AYLISPRSNL GLFIKKPFIK FICHTASYLT FLFMLLLASQ HIVRTDLHVQ GPPP TVVEW MILPWVLGFI WGEIKEMWDG GFTEYIHDWW NLMDFAMNSL YLATISLKIM AYVKYNGSRP REEWEMWHPT LIAEA LFAI SNILSSLRLI SLFTANSHLG PLQISLGRML LDILKFLFIY CLVLLAFANG LNQLYFYYET RAIDEPNNCK GIRCEK QNN AFSTLFETLQ SLFWSVFGLL NLYVTNVKAR HEFTEFVGAT MFGTYNVISL VVLLNMLIAM MNNSYQLIAD HADIEWK FA RTKLWMSYFD EGGTLPPPFN IIPSPKSFLY LGNWFNNTFC PKRDPDGRRR RRNLRSFTER NADSLIQNQH YQEVIRNL V KRYVAAMIRN SKTHEGLTEE NFKELKQDIS SFRYEVLDLL GNRK

UniProtKB: Short transient receptor potential channel 5

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Macromolecule #2: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: PHOSPHATIDYLETHANOLAMINE

MacromoleculeName: PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 4 / Number of copies: 4 / Formula: PTY
Molecular weightTheoretical: 734.039 Da
Chemical component information

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 4 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #6: (-)-englerin A

MacromoleculeName: (-)-englerin A / type: ligand / ID: 6 / Number of copies: 4 / Formula: A1L55
Molecular weightTheoretical: 442.545 Da

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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

Concentration0.9 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaCLSodium chloride
50.0 mMHEPES2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethanesulfonic acid
1.0 mMDTTDithiothreitol
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
DetailsHomogeneous sample

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.65 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.7000000000000001 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4-4.6) / Number images used: 37807
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4-4.6)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4-4.6)
Final 3D classificationNumber classes: 4 / Software - Name: cryoSPARC (ver. 4.4-4.6)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: Other / Chain - Initial model type: in silico model / Details: ModelAngelo
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9rrm:
Human TRPC5 in complex with (-) englerin A, full occupancy, state 1, on 290 nm gold foil holes (HexAuFoil)

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