Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site.
Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site.
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DOI：
10.1038/s42003-020-01437-8
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发表时间：
2020-11-23
影响因子：
5.9
通讯作者：
Bon RS
中科院分区：
文献类型：
--
作者：
Wright DJ;Simmons KJ;Johnson RM;Beech DJ;Muench SP;Bon RS
TRPC1/4/5通道是非特异性阳离子通道，与多种疾病有关，TRPC1/4/5抑制剂最近进入临床试验。然而，基础研究和转化研究需要更好地了解TRPC1/4/5通道受内源性和外源性因素的调控。尽管已经报道了几种有效和选择性的TRPC1/4/5调节剂，但缺乏对其作用模式的机制见解仍然是开发新的化学探针和候选药物的障碍。基于黄嘌呤的调节剂包括迄今为止描述的最有效和选择性的TRPC1/4/5抑制剂，以及TRPC5激活剂。我们之前的研究表明，到目前为止，黄嘌呤与TRPC1/4/5通道的一个难以捉摸的口袋相互作用，这对通道门控至关重要。在这里，我们报道了一个小分子结合的TRPC1/4/5通道-人TRPC5与黄嘌呤pico145复合物的结构-至3.0 Å。我们发现Pico145结合到TRPC5的一个保守的脂质结合位点，在那里它取代了一个结合的磷脂。我们的研究结果解释了基于黄嘌呤的TRPC1/4/5调节剂的作用方式，并提出了TRPC1/4/5被（磷）脂质和Zn2+离子等内源性因子调节的结构基础。这些研究为新一代TRPC1/4/5调制器基于结构的设计奠定了基础。Wright等人报道了人类TRPC1/4/5通道与基于黄嘌呤的TRPC5抑制剂Pico145复合物的第一个结构。他们发现Pico145与TRPC5的一个保守的脂质结合位点结合，在那里它取代了磷脂。本研究揭示了基于黄嘌呤的TRPC1/4/5调节剂的作用机制。
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 Zn2+ ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators. Wright et al. report the first structure of a human TRPC1/4/5 channel in complex with a xanthine-based TRPC5 inhibitor Pico145. They find that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a phospholipid. This study provides insights into the mechanism-of-action of xanthine-based TRPC1/4/5 modulators.
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DOI：
10.1002/anie.201411511
发表时间：
2015-03-16
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Akbulut Y;Gaunt HJ;Muraki K;Ludlow MJ;Amer MS;Bruns A;Vasudev NS;Radtke L;Willot M;Hahn S;Seitz T;Ziegler S;Christmann M;Beech DJ;Waldmann H
通讯作者：
Waldmann H
影响因子：
5.3
作者：
Lepannetier S;Gualdani R;Tempesta S;Schakman O;Seghers F;Kreis A;Yerna X;Slimi A;de Clippele M;Tajeddine N;Voets T;Bon RS;Beech DJ;Tissir F;Gailly P
通讯作者：
Gailly P
影响因子：
4.1
作者：
通讯作者：
--
影响因子：
7.7
作者：
Fan C;Choi W;Sun W;Du J;Lü W
通讯作者：
Lü W
影响因子：
5.6
作者：
Hawkins, Paul C. D.;Nicholls, Anthony
通讯作者：
Nicholls, Anthony