8TF4
Wildtype rabbit TRPV5 into nanodiscs in the presence of PI(4,5)P2 and econazole
Summary for 8TF4
| Entry DOI | 10.2210/pdb8tf4/pdb |
| EMDB information | 41219 |
| Descriptor | Transient receptor potential cation channel subfamily V member 5, ERGOSTEROL, 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (4 entities in total) |
| Functional Keywords | trpv5, trp channel, pi(4, 5)p2, econazole, membrane protein |
| Biological source | Oryctolagus cuniculus (rabbit) |
| Total number of polymer chains | 4 |
| Total formula weight | 345902.74 |
| Authors | De Jesus-Perez, J.J.,Fluck, E.C.,Moiseenkova-Bell, V.Y. (deposition date: 2023-07-07, release date: 2024-01-10, Last modification date: 2024-02-14) |
| Primary citation | De Jesus-Perez, J.J.,Gabrielle, M.,Raheem, S.,Fluck, E.C.,Rohacs, T.,Moiseenkova-Bell, V.Y. Structural mechanism of TRPV5 inhibition by econazole. Structure, 32:148-156.e5, 2024 Cited by PubMed Abstract: The calcium-selective TRPV5 channel activated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] is involved in calcium homeostasis. Recently, cryoelectron microscopy (cryo-EM) provided molecular details of TRPV5 modulation by exogenous and endogenous molecules. However, the details of TRPV5 inhibition by the antifungal agent econazole (ECN) remain elusive due to the low resolution of the currently available structure. In this study, we employ cryo-EM to comprehensively examine how the ECN inhibits TRPV5. By combining our structural findings with site-directed mutagenesis, calcium measurements, electrophysiology, and molecular dynamics simulations, we determined that residues F472 and L475 on the S4 helix, along with residue W495 on the S5 helix, collectively constitute the ECN-binding site. Additionally, the structure of TRPV5 in the presence of ECN and PI(4,5)P, which does not show the bound activator, reveals a potential inhibition mechanism in which ECN competes with PI(4,5)P, preventing the latter from binding, and ultimately pore closure. PubMed: 38141613DOI: 10.1016/j.str.2023.11.012 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.86 Å) |
Structure validation
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