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Structure paper

Title(-)-Englerin A binding to human TRPC5 exposes an aromatic interaction network in channel activation.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateApr 29, 2026
AuthorsSebastian A Porav / Alexandra Ptakova / Claudia C Bauer / Kasia L R Hammond / David J Beech / Viktorie Vlachova / Stephen P Muench / Robin S Bon /
PubMed AbstractTRPC4/5 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.
External linksNat Commun / PubMed:42056091
MethodsEM (single particle)
Resolution2.3 - 3.2 Å
Structure data

54186

9rrf

EMDB-54186, PDB-9rrf:
TRPC5 apo cryoEM map in the presence of pluronic acid (PA), state 2
Method: EM (single particle) / Resolution: 2.3 Å

54187

9rrm

EMDB-54187, PDB-9rrm:
Human TRPC5 in complex with (-) englerin A, full occupancy, state 1, on 290 nm gold foil holes (HexAuFoil)
Method: EM (single particle) / Resolution: 2.5 Å

54188

9rrn

EMDB-54188, PDB-9rrn:
Human TRPC5 in complex with (-) englerin A, full occupancy, state 2, on 290 nm gold foil holes (HexAuFoil)
Method: EM (single particle) / Resolution: 2.5 Å

54189

9rro

EMDB-54189, PDB-9rro:
Human TRPC5 in complex with (-) englerin A, full occupancy, intermediary desensitized state
Method: EM (single particle) / Resolution: 2.8 Å

54193

9rrq

EMDB-54193, PDB-9rrq:
Human TRPC5 in complex with (-) englerin A, partial occupancy (2EA:2LIP stoichiometry) state 1
Method: EM (single particle) / Resolution: 2.9 Å

54204

9rru

EMDB-54204, PDB-9rru:
Human TRPC5 in complex with (-) englerin A, mixed occupancy, state 1
Method: EM (single particle) / Resolution: 3.2 Å

54218

9rsg

EMDB-54218, PDB-9rsg:
Human TRPC5 in complex with (-) englerin A, mixed occupancy_2, state 2
Method: EM (single particle) / Resolution: 3.2 Å

54219

9rsh

EMDB-54219, PDB-9rsh:
Human TRPC5 in complex with (-) englerin A, mixed occupancy, state 2
Method: EM (single particle) / Resolution: 3.0 Å

54291

9rvv

EMDB-54291, PDB-9rvv:
Human TRPC5 in complex with (-) englerin A, partial occupancy (2EA:2LIP stoichiometry) state 2
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-YZY:
(2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-CA:
Unknown entry

PDB-1l55:
ANALYSIS OF THE INTERACTION BETWEEN CHARGED SIDE CHAINS AND THE ALPHA-HELIX DIPOLE USING DESIGNED THERMOSTABLE MUTANTS OF PHAGE T4 LYSOZYME

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Ion Channel / apo / TRPC5 / (-) englerin A / agonist

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