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Shedding light on the principles of G protein selectivity

September 19, 2018

A “structural switch,” allowing for maximum efficiency in the visual system

Selective coupling of G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) to specific Gα-protein subtypes is critical to transform extracellular signals, carried by natural ligands and clinical drugs, into cellular responses. At the center of this transduction event lies the formation of a signaling complex between the receptor and G protein. We report the crystal structure of light-sensitive GPCR rhodopsin bound to an engineered mini-Go protein. The conformation of the receptor is identical to all previous structures of active rhodopsin, including the complex with arrestin. Thus, rhodopsin seems to adopt predominantly one thermodynamically stable active conformation, effectively acting like a “structural switch,” allowing for maximum efficiency in the visual system. Furthermore, our analysis of the well-defined GPCR–G protein interface suggests that the precise position of the carboxyl-terminal “hook-like” element of the G protein (its four last residues) relative to the TM7/helix 8 (H8) joint of the receptor is a significant determinant in selective G protein activation.

The structure of rhodopsin bound to mini-Go adds a key piece to the gallery of states along its activation pathway, making rhodopsin the best-described GPCR in terms of structure. The authors can now sequentially track the conformations of a GPCR from its inactive state to agonist-induced activation, G protein coupling, and binding to arrestin. Furthermore, the structure provides new insights into the binding interface between activated GPCRs and Gi/o proteins. This information advances the understanding of GPCR–G protein selectivity and how GPCR conformations promote certain signaling pathways.


Figure. The top panel depicts the structural intermediates during rhodopsin activation. Light-induced retinal isomerization results in the formation of a predefined binding pocket for a Gi/o protein or arrestin. On the other hand, the bottom panel depicts how binding of diffusible ligands results in the formation of transient active GPCR conformations with higher conformational heterogeneity than active rhodopsin. In this case, the G protein likely selects and stabilizes a suitable conformation of the binding pocket from this ensemble.

Reference: Tsai, C. J., F. Pamula, R. Nehme, J. Muhle, T. Weinert, T. Flock, P. Nogly, P. C. Edwards, B. Carpenter, T. Gruhl, P. Ma, X. Deupi, J. Standfuss, C. G. Tate and G. F. X. Schertler (2018). Crystal structure of rhodopsin in complex with a mini-G(o) sheds light on the principles of G protein selectivity. Sci. Adv. 4. (10.1126/sciadv.aat7052) Tsai-2018.

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