GPCR

History and significance

With the determination of the first structure of the complex between a G-protein coupled receptor (GPCR) and a G-protein trimer (Gαβγ) in 2011 a new chapter of GPCR research was opened for structural investigations of global switches with more than one protein being investigated. The previous breakthroughs involved determination of the crystal structure of the first GPCR, rhodopsin, in 2000 and the crystal structure of the first GPCR with a diffusible ligand (β₂AR) in 2007. The way in which the seven transmembrane helices of a GPCR are arranged into a bundle was suspected based on the low-resolution model of frog rhodopsin from cryogenic electron microscopy studies of the two-dimensional crystals. The crystal structure of rhodopsin, that came up three years later, was not a surprise apart from the presence of an additional cytoplasmic helix H8 and a precise location of a loop covering retinal binding site. However, it provided a scaffold which was hoped to be a universal template for homology modeling and drug design for other GPCRs – a notion that proved to be too optimistic.