Biological complexity: the role of G protein receptors (Introduction)

by David Turell , Thursday, March 19, 2020, 21:22 (1499 days ago) @ David Turell

A study generally shows how they function at the molecular level:

https://phys.org/news/2020-03-glucagon-receptor-reveal-protein-specificity.html

"G protei"n-coupled receptors (GPCRs) play essential roles in cell signal transduction and serve as important therapeutic targets for a large number of diseases. Upon binding to extracellular agonists, GPCRs stimulate various signaling pathways by recruiting different G proteins (Gs, Gi, Gq, etc.) to mediate a wide variety of physiological functions. The selective coupling between a GPCR and specific G proteins is critical for the biological action of the receptor.

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"GCGR, a member of the class B GPCR family, is critical to glucose homeostasis by triggering the release of glucose from the liver, making it a potential drug target for type 2 diabetes and obesity.

"Although GCGR canonically exerts its physiological action through Gs signaling, it can also couple to other G proteins such as Gi and Gq, leading to diverse cellular responses. In 2017 and 2018, the scientists at SIMM determined the crystal structures of the full-length GCGR bound to a negative allosteric modulator or a partial peptide agonist, providing insights into signal recognition and modulation of class B GPCRs.

"This time, the scientists made further progress by solving the complex structures of GCGR bound to two transducer proteins with opposing biological activities. This study offers valuable insights into pleiotropic GPCR-G protein coupling and G protein specificity. Notably, it revealed that the sixth transmembrane helix (helix VI) of GCGR adopts a similar outward shift in the two G protein-bound GCGR structures, forming a common binding cavity to accommodate Gs and Gi. This is contrary to the hypothesis based on the previously determined GPCR-G protein complex structures, which proposed that the positional difference of helix VI is a major discriminator in the coupling specificity of Gs and Gi.

"The common G protein binding pocket observed in the GCGR-G protein complex structures is consistent with the signaling pleiotropy of GCGR and allows for maximal efficiency in activating various pathways. Although GCGR couples to both G proteins through the common pocket, it does so with different interaction patterns, which account for G protein specificity. The measured interaction interface between GCGR and Gs is much larger than for Gi, resulting in higher binding affinity of Gs to the receptor. This offers a structural basis for the preferential coupling of GCGR to Gs.***

"The results show that conformational differences of intracellular loops and residue side chains in the receptor are sufficient to guide G protein selectivity. The interactions contributed by the second intracellular loop (ICL2) and helix VII/VIII junction of the receptor play a crucial role in Gs coupling, while the other two intracellular loops, ICL1 and ICL3, and the receptor hydrophobic intracellular binding cavity are more important for Gi recognition."

Comment: Another example of protein molecules automatically reacting to manage a process in glucose metabolism