Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in a variety of physiological and pathophysiological processes, putting TRPV2 on the list of important drug targets. Yet, specific TRPV2 agonists and antagonists are currently unavailable. Their development requires a precise knowledge of how the currently known non-specific small molecules interact with TRPV2 at the molecular level. Here we present TRPV2 structures in ligand-bound states resolved by cryo-electron microscopy in the presence of 2-aminoethoxydiphenyl borate (2-ABP), 2-APB with doxorubicin (DOXO), and ruthenium red (RR). We identified a novel 2-APB drug binding site between the S5 helix and S4-S5 linker on two adjacent TRPV2 monomers and determined the mechanism of TRPV2 pore block by RR. We also showed that a large organic molecule like DOXO can enter the TRPV2 pore in the presence of 2-APB. Additionally, we discovered a structural lipid bound in a unique position in the vanilloid pocket, which is absent in the 2-APB-bound state of the channel, allowing us to propose a model for TRPV2 channel gating. Together, this work provides a further understanding of TRPV2 function and a structural framework for the development of TRPV2-specific modulators.

中文翻译：

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低温电磁波揭示TRPV2与小分子和脂质的相互作用

瞬态受体电位香草酸2（TRPV2）在多种生理和病理生理过程中起着至关重要的作用，使TRPV2成为重要的药物靶标。但是，目前尚无特定的TRPV2激动剂和拮抗剂。它们的发展需要对目前已知的非特异性小分子如何在分子水平上与TRPV2相互作用的精确知识。在这里，我们介绍在存在2-氨基乙氧基二苯基硼酸盐（2-ABP），2-APB与阿霉素（DOXO）和钌红（RR）的情况下，通过低温电子显微镜解析的配体结合状态的TRPV2结构。我们在两个相邻的TRPV2单体上的S5螺旋和S4-S5接头之间鉴定了一个新型的2-APB药物结合位点，并通过RR确定了TRPV2孔阻断的机制。我们还表明，在2-APB存在下，像DOXO这样的大有机分子可以进入TRPV2孔。此外，我们发现了在类脂香囊袋中唯一位置上结合的结构脂质，该脂质在通道的2-APB结合状态中不存在，从而使我们能够提出TRPV2通道门控模型。在一起，这项工作提供了对TRPV2功能的进一步了解，以及开发TRPV2特异性调节剂的结构框架。