G protein-coupled receptors (GPCRs) are a large superfamily of proteins embedded on the plasma membrane of cells. They function as cellular receivers for messages conveyed by extracellular chemicals or, in the case of opsin, photons of light. These messages are subsequently translated into a cellular response, which initiates with the activation of an intracellular signaling partner.

Left panel: cartoon representation of a GPCR embedded in a membrane bilayer, bound to a ligand and a heterotrimeric G protein. Right panel: X-ray structure of the beta2-adrenergic receptor solved in complex with a heterotrimeric Gs protein (PDB ID: 3SN6), embedded in a molecular model of the membrane bilayer. 

GPCRs derive their name from the fact that their canonical signaling begins with the activation of intracellular heterotrimeric G proteins. However, it has been subsequently recognized that GPCRs also trigger G protein-independent signaling (e.g. by coupling to arrestins).

Molecules that naturally activate G protein-coupled receptors encompass a wealth of endogenous substances – for instance hormones, neurotransmitters and neuromodulators – as well as exogenous substances – for instance those responsible for olfactive or taste stimuli. A great percentage of the prescription drugs, as well as drugs of abuse, act either directly to indirectly through GPCRs, and have the ultimate effect of modulating GPCR signaling.

The human genome has genes for about 1000 different GPCRs. The entire superfamily can be divided into a number of different families, the largest of which is known as the rhodopsin family (also Class A or Family I).

GPCR Structures. From the structural perspective, GPCRs are constituted by a single polypeptide chain that spans seven times the plasma membrane with seven helical structures (transmembrane domains). The seven transmembrane domains fold into a bundle with one opening facing the cytosol and the other facing the extracellular milieu. The cytosolic opening is the site to which the intracellular signaling partners of the receptors bind (e.g. heterotrimeric G proteins and arrestins). The extracellular opening, for many GPCRs, is the site to which the receptor modulators bind.

Due to the high pharmaceutical relevance of GPCRs, there is great interest in the experimental elucidation of their structures. Most of the structures have been solved through X-ray crystallography. The first crystal structure of a GPCR, namely bovine rhodopsin, was solved in 2000. In 2007, it was the turn of the beta 2-adrenergic receptor. The structures of many other receptors have been solved since then. Since 2018, GPCR structures have been solved through electron microscopy as well, most of which in complex with intracellular signaling partners or with large protein ligands.

 As of September 16, 2021, a total of 597 structures have been solved for 110 different GPCRs – information from GPCRdb.

The 3D structures can be applied to the discovery of new chemicals that can bind to the receptors, and that can be potentially be developed into pharmacological probes and ultimately drugs. For instance virtual screening campaigns based on molecular docking can be conducted to identify novel lead binders.

Moreover, through the homology modeling technique, The 3D structures can be also be applied to the construction of 3D models for those receptors for which experimental structures have yet to be elucidated – the great majority of members of the GPCR superfamily.