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Do All Roads Lead to Rome in G-Protein Activation?

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High-resolution structural studies on G-protein-coupled receptors (GPCRs) have flourished recently, providing long-sought insights into the dynamic process of guanine nucleotide-binding protein (G-protein) activation. In parallel, analogous studies are starting to shed light on how the same G-proteins are activated by non-GPCR proteins. Can we learn about common themes and variations in G-protein activation from them?

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Activation of G-Protein by GPCR and Non-GPCR GEFs

From the first atomic resolution structure of a GPCR–G-protein complex (β2 adrenergic receptor with Gs) reported in 2011 [1] and other holocomplex structures reported later (e.g., [11]), the most striking conformational rearrangement observed is a large separation of the Ras-like and helical domains of Gα. Such interdomain separation does not seem to be the principal trigger for nucleotide release, but rather, a sequel to allosteric mechanisms that trigger the release [4]; it facilitates the

Acknowledgments

The authors wish to apologize for not citing many important publications on this topic due to the limit of references allowed. P.G. is supported by NIH grants CA238042, AI141630, CA100768, and CA160911, and M.G-M. is supported by NIH grants GM108733, GM130120, GM136132, and MH118745.

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