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-Structure paper
タイトル | Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site. |
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ジャーナル・号・ページ | Commun Biol, Vol. 3, Issue 1, Page 704, Year 2020 |
掲載日 | 2020年11月23日 |
![]() | David J Wright / Katie J Simmons / Rachel M Johnson / David J Beech / Stephen P Muench / Robin S Bon / ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (単粒子) |
解像度 | 2.8 - 3.0 Å |
構造データ | EMDB-10903, PDB-6ysn: ![]() EMDB-10909: ![]() EMDB-10910: |
化合物 | ![]() ChemComp-PJQ: |
由来 |
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![]() | MEMBRANE PROTEIN / Ion channel / small molecule / inhibitor / tetramer |