The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein

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Science  26 Apr 2019:
Vol. 364, Issue 6438, pp. 389-394
DOI: 10.1126/science.aav0778

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The architecture of a signaling hub

Adenylyl cyclases (ACs) respond to a variety of inputs to generate the signaling molecule cyclic adenosine monophosphate. ACs are regulated by G proteins, which are activated by upstream receptors. Qi et al. determined the structure of bovine membrane AC9 bound to an activated G protein αs subunit by cryo–electron microscopy at 3.4-angstrom resolution. The structure provides the full architecture of AC9, including a helical domain that connects the transmembrane and catalytic domains. The model reveals how the domains interact to regulate enzymatic activity, including suggesting a mechanism of self-inhibition.

Science, this issue p. 389


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.

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