Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland.
Science. 2019 Apr 26;364(6438):389-394. doi: 10.1126/science.aav0778.
Membrane-integral adenylyl cyclases (ACs) are key enzymes in mammalian heterotrimeric GTP-binding protein (G protein)-dependent signal transduction, which is important in many cellular processes. Signals received by the G protein-coupled receptors are conveyed to ACs through G proteins to modulate the levels of cellular cyclic adenosine monophosphate (cAMP). Here, we describe the cryo-electron microscopy structure of the bovine membrane AC9 bound to an activated G protein αs subunit at 3.4-angstrom resolution. The structure reveals the organization of the membrane domain and helical domain that spans between the membrane and catalytic domains of AC9. The carboxyl-terminal extension of the catalytic domain occludes both the catalytic and the allosteric sites of AC9, inducing a conformation distinct from the substrate- and activator-bound state, suggesting a regulatory role in cAMP production.
膜整合腺苷酸环化酶（AC）是哺乳动物异三聚体 G 蛋白偶联受体（GPCR）依赖的信号转导中的关键酶，在许多细胞过程中都很重要。G 蛋白偶联受体接收的信号通过 G 蛋白传递到 AC 以调节细胞环腺苷酸（cAMP）的水平。在这里，我们描述了在 3.4 埃分辨率下与激活的 G 蛋白αs 亚基结合的牛膜 AC9 的冷冻电子显微镜结构。该结构揭示了 AC9 的膜结构域和螺旋结构域的组织，该结构域跨越 AC9 的膜和催化结构域之间。催化结构域的羧基末端延伸部分封闭了 AC9 的催化和变构部位，诱导与底物和激活剂结合状态不同的构象，提示在 cAMP 产生中起调节作用。
