A recent break-through paper has revealed for the first time the high-resolution, three-dimensional structure of a mammalian trans-membrane adenylyl cyclase (tmAC) obtained by cryo-electronmicroscopy (cryo-EM). Reporting the structure of adenylyl cyclase 9 (AC9) in complex with activated Gsα, the cryo-EM study revealed that AC9 has three functionally interlinked, yet structurally distinct domains. The array of the twelve transmembrane helices is connected to the cytosolic catalytic core by two helical segments that are stabilized through the formation of a parallel coiled-coil. Surprisingly, in the presence of Gsα, the isoform-specific carboxyl-terminal tail of AC9 occludes the forskolin- as well as the active substrate-sites, resulting in marked autoinhibition of the enzyme. As AC9 has the lowest primary sequence homology with the eight further mammalian tmAC paralogues, it appears to be the best candidate for selective pharmacologic targeting. This is now closer to reality as the structural insight provided by the cryo-EM study indicates that all of the three structural domains are potential targets for bioactive agents. The present paper summarizes for molecular physiologists and pharmacologists what is known about the biological role of AC9, considers the potential modes of physiologic regulation, as well as pharmacologic targeting on the basis of the high-resolution cryo-EM structure. The translational potential of AC9 is considered upon highlighting the current state of genome-wide association screens, and the corresponding experimental evidence. Overall, whilst the high- resolution structure presents unique opportunities for the full understanding of the control of AC9, the data on the biological role of the enzyme and its translational potential are far from complete, and require extensive further study.

中文翻译：

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腺苷酸环化酶 9 的冷却及其翻译潜力。

最近的一篇突破性论文首次揭示了通过冷冻电子显微镜 (cryo-EM) 获得的哺乳动物跨膜腺苷酸环化酶 (tmAC) 的高分辨率三维结构。冷冻电镜研究报告了腺苷酸环化酶 9 (AC9) 与活化的 Gsα 复合物的结构，揭示了 AC9 具有三个功能相互关联但结构不同的域。十二个跨膜螺旋的阵列通过两个螺旋段连接到细胞溶质催化核心，这些螺旋段通过形成平行盘绕线圈而稳定。令人惊讶的是，在 Gsα 存在的情况下，AC9 的异构体特异性羧基末端尾部封闭了毛喉素和活性底物位点，导致酶的显着自身抑制。由于 AC9 与八个其他哺乳动物 tmAC 旁系同源物的一级序列同源性最低，因此它似乎是选择性药理学靶向的最佳候选者。现在这更接近现实，因为冷冻电镜研究提供的结构洞察表明所有三个结构域都是生物活性剂的潜在目标。本文为分子生理学家和药理学家总结了对 AC9 生物学作用的了解，考虑了生理调节的潜在模式，以及基于高分辨率冷冻电镜结构的药理学靶向。在突出显示全基因组关联筛选的当前状态和相应的实验证据后，考虑了 AC9 的转化潜力。全面的，