Structural Aspects of GPCR-G Protein Coupling

Abstract

G protein-coupled receptors (GPCRs) are membrane receptors; approximately 40% of drugs on the market target GPCRs. A precise understanding of the activation mechanism of GPCRs would facilitate the development of more effective and less toxic drugs. Heterotrimeric G proteins are important molecular switches in GPCR-mediated signal transduction. An agonist-activated receptor interacts with specific sites on G proteins and promotes the release of GDP from the Gα subunit. Because of the important biological role of the GPCR-G protein coupling, conformational changes in the G protein upon receptor coupling have been of great interest. One of the most important questions was the interface between the GPCR and G proteins and the structural mechanism of GPCR-induced G protein activation. A number of biochemical and biophysical studies have been performed since the late 80s to address these questions; there was a significant breakthrough in 2011 when the crystal structure of a GPCR-G protein complex was solved. This review discusses the structural aspects of GPCR-G protein coupling by comparing the results of previous biochemical and biophysical studies to the GPCR-G protein crystal structure.

Keywords: G protein; GPCR; Structure.

Fig. 1.. Crystal structures of Gtαβγ heterotrimer with GDP (A) and Gtα subunit with GTPγS (B). A. The crystal structure of inactive resting state Gtαβγ heterotrimer with GDP is adapted from PDB file (PDB: 1GOT). Green: Gα, Cyan: Gβ, Magenta: Gγ, red: GDP. B. The crystal structure of active Gtα subunit with GTPγS is adapted from PDB file (PDB: 1TND). Green: Gα, Red: GTPβS.

Fig. 2.. Interaction between GPCR and G protein heterotrimer. A. Predicted model of GPCR-G protein coupling. Orange: GPCR, Green: Gα, Cyan: Gβ, Magenta: Gγ, red: GDP. B. The crystal structure of β2AR-Gs protein complex (PDB: 3SN6). Orange: β2AR, Green: Gα, Cyan: Gβ, Magenta: Gγ.

Fig. 3.. Comparison of Ras-like domains of inactive-GDP-bound Gα subunit (Grey) (PDB:1GP2) and intermediate-receptor-bound nucleotide- free Gα subunit (Green) (PDB: 3SN6). Red: GDP.