9RRQ
Human TRPC5 in complex with (-) englerin A, partial occupancy (2EA:2LIP stoichiometry) state 1
This is a non-PDB format compatible entry.
Summary for 9RRQ
| Entry DOI | 10.2210/pdb9rrq/pdb |
| EMDB information | 54193 |
| Descriptor | Short transient receptor potential channel 5, CALCIUM ION, PHOSPHATIDYLETHANOLAMINE, ... (7 entities in total) |
| Functional Keywords | trpc5, (-) englerin a, agonist, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 363419.28 |
| 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 (2.9 Å) |
Structure validation
Download full validation report
