6YSN
Human TRPC5 in complex with Pico145 (HC-608)
Summary for 6YSN
| Entry DOI | 10.2210/pdb6ysn/pdb |
| EMDB information | 10903 |
| Descriptor | Maltose/maltodextrin-binding periplasmic protein,Short transient receptor potential channel 5, 7-[(4-chlorophenyl)methyl]-3-methyl-1-(3-oxidanylpropyl)-8-[3-(trifluoromethyloxy)phenoxy]purine-2,6-dione (2 entities in total) |
| Functional Keywords | ion channel, small molecule, inhibitor, tetramer, membrane protein |
| Biological source | Escherichia coli (strain K12) More |
| Total number of polymer chains | 4 |
| Total formula weight | 525139.63 |
| Authors | Wright, D.J.,Johnson, R.M.,Muench, S.P.,Bon, R.S. (deposition date: 2020-04-22, release date: 2020-12-02, Last modification date: 2024-10-16) |
| Primary citation | Wright, D.J.,Simmons, K.J.,Johnson, R.M.,Beech, D.J.,Muench, S.P.,Bon, R.S. Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site. Commun Biol, 3:704-704, 2020 Cited by PubMed Abstract: TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. Xanthine-based modulators include the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Here we report the structure of a small-molecule-bound TRPC1/4/5 channel-human TRPC5 in complex with the xanthine Pico145-to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators. PubMed: 33230284DOI: 10.1038/s42003-020-01437-8 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
Download full validation report
