9RRF
TRPC5 apo cryoEM map in the presence of pluronic acid (PA), state 2
Summary for 9RRF
| Entry DOI | 10.2210/pdb9rrf/pdb |
| EMDB information | 54186 |
| Descriptor | Short transient receptor potential channel 5, ZINC ION, (2S)-2-(hexadecanoyloxy)-3-hydroxypropyl (9Z)-octadec-9-enoate, ... (6 entities in total) |
| Functional Keywords | ion channel, apo, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 363724.08 |
| Authors | |
| Primary citation | Porav, S.A.,Ptakova, A.,Bauer, C.C.,Hammond, K.L.R.,Beech, D.J.,Vlachova, V.,Muench, S.P.,Bon, R.S. (-)-Englerin A binding to human TRPC5 exposes an aromatic interaction network in channel activation. Nat Commun, 2026 Cited by PubMed 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 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. PubMed: 42056091DOI: 10.1038/s41467-026-71840-y PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.3 Å) |
Structure validation
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