Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands
Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands
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DOI：
10.1038/s41589-022-01139-8
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发表时间：
2022-09
影响因子：
14.8
通讯作者：
Nannan Su;Wenxuan Zhen;Heng Zhang;Lingyi Xu;Yitian Jin;Xiaoying Chen;Cheng Zhao;Qinrui Wang;Xinyan Wang;Shaowei Li;Han Wen;Wei Yang;Jiangtao Guo;Fan Yang
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文献类型：
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作者：
Nannan Su;Wenxuan Zhen;Heng Zhang;Lingyi Xu;Yitian Jin;Xiaoying Chen;Cheng Zhao;Qinrui Wang;Xinyan Wang;Shaowei Li;Han Wen;Wei Yang;Jiangtao Guo;Fan Yang
瞬时受体电位香草酸2（TRPV2）离子通道是一种多模式受体，广泛参与许多生理和病理过程。尽管已经鉴定出许多 TRPV2 调节剂，但 TRPV2 是否以及如何受内源性脂质调节仍不清楚。在这里，我们报告了 TRPV2 香草酸结合袋 (VBP) 内的内源性胆固醇分子，具有“头朝下、尾部朝上”的结构，使用冷冻电镜分辨率为 3.2 Å。胆固醇结合会拮抗 TRPV2 的配体激活，在 2.9 Å 处解析，TRPV2 可以被甲基-β-环糊精 (MβCD) 从 VBP 中去除。我们还观察到雌二醇 (E2) 通过 2-氨基乙氧基二苯基硼酸盐 (2-APB) 增强 TRPV2 激活，2-APB 是 TRP 通道的经典工具化合物。我们的冷冻电镜结构（分辨率为 2.8–3.3 Å）进一步表明 E2 如何干扰胆固醇结合，以及 2-APB 如何分别在有 E2 或没有 E2 和内源胆固醇的情况下在 VBP 内结合。因此，我们的研究为TRPV2中抑制性内源胆固醇和兴奋性外源2-APB的配体识别奠定了结构基础。
The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being identified, whether and how TRPV2 is regulated by endogenous lipids remains elusive. Here, we report an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2, with a ‘head down, tail up’ configuration, resolved at 3.2 Å using cryo-EM. Cholesterol binding antagonizes ligand activation of TRPV2, which is removed from VBP by methyl-β-cyclodextrin (MβCD) as resolved at 2.9 Å. We also observed that estradiol (E2) potentiated TRPV2 activation by 2-aminoethoxydiphenyl borate (2-APB), a classic tool compound for TRP channels. Our cryo-EM structures (resolved at 2.8–3.3 Å) further suggest how E2 disturbed cholesterol binding and how 2-APB bound within the VBP with E2 or without both E2 and endogenous cholesterol, respectively. Therefore, our study has established the structural basis for ligand recognition of the inhibitory endogenous cholesterol and excitatory exogenous 2-APB in TRPV2.