Editing G protein-coupled receptor (section)

==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 (β<sub>2</sub>AR) 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.{{cn|date=April 2025}}

Results 7 years later were surprising because the crystallization of β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR) with a diffusible ligand revealed quite a different shape of the receptor extracellular side than that of rhodopsin. This area is important because it is responsible for the ligand binding and is targeted by many drugs. Moreover, the ligand binding site was much more spacious than in the rhodopsin structure and was open to the exterior. In the other receptors crystallized shortly afterwards the binding side was even more easily accessible to the ligand. New structures complemented with biochemical investigations uncovered mechanisms of action of molecular switches which modulate the structure of the receptor leading to activation states for agonists or to complete or partial inactivation states for inverse agonists.<ref name="Trzaskowski2012" />

The 2012 [[Nobel Prize in Chemistry]] was awarded to [[Brian Kobilka]] and [[Robert Lefkowitz]] for their work that was "crucial for understanding how G protein-coupled receptors function".<ref name="Nobel committee,2012">{{cite news|vauthors=((Royal Swedish Academy of Sciences))|title=The Nobel Prize in Chemistry 2012 Robert J. Lefkowitz, Brian K. Kobilka|url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/press.html|access-date=10 October 2012|date=10 October 2012}}</ref> There have been at least [[List of Nobel laureates in Physiology or Medicine|seven other Nobel Prizes]] awarded for some aspect of G protein–mediated signaling. As of 2012, two of the top ten global best-selling drugs ([[fluticasone propionate/salmeterol|Advair Diskus]] and [[aripiprazole|Abilify]]) act by targeting G protein-coupled receptors.<ref name="urlwww.imshealth.com">{{cite journal | vauthors = Lindsley CW | title = The top prescription drugs of 2012 globally: biologics dominate, but small molecule CNS drugs hold on to top spots | journal = ACS Chemical Neuroscience | volume = 4 | issue = 6 | pages = 905–7 | date = June 2013 | pmid = 24024784 | pmc = 3689196 | doi = 10.1021/cn400107y }}</ref>