Abstract
Agonist binding is related to a series of motions in G protein-coupled receptors (GPCRs) that result in the separation of transmembrane helices III and VI at their cytosolic ends and subsequent G protein binding. A large number of smaller motions also seem to be associated with activation. Most helices in GPCRs are highly irregular and often contain kinks, with extensive literature already available about the role of prolines in kink formation and the precise function of these kinks. GPCR transmembrane helices also contain many α-bulges. In this article we aim to draw attention to the role of these α-bulges in ligand and G-protein binding, as well as their role in several aspects of the mobility associated with GPCR activation. This mobility includes regularization and translation of helix III in the extracellular direction, a rotation of the entire helix VI, an inward movement of the helices near the extracellular side, and a concerted motion of the cytosolic ends of the helices that makes their orientation appear more circular and that opens up space for the G protein to bind. In several cases, α-bulges either appear or disappear as part of the activation process.
Highlights
G protein-coupled receptors (GPCRs) are important targets for the pharmaceutical industry and have been studied extensively in vivo, in vitro, and in silico
The way we use the random forest (RF) method to analyze GPCR structure characteristics in distance space requires that the hypotheses put forward logically lead to classifications of existing GPCR structures involving a limited number of groups
Any hypothesis related to the activation process will be a good candidate, because the GPCR structure community has been working hard to shed light on this process by solving the structures of GPCRs with bound agonists, partial agonists, etc. and GPCR structures in the presence and absence of G proteins
Summary
G protein-coupled receptors (GPCRs) are important targets for the pharmaceutical industry and have been studied extensively in vivo, in vitro, and in silico. Their importance is illustrated by the fact that PubMed [1] lists around 500 reviews relating to GPCRs every year. Most the GPCR structures solved so far are from the rhodopsin-like family—normally referred to as the. This article exclusively examines Class A GPCRs, so each time the acronym. GPCR is used, it should be interpreted as “Class A GPCR”.
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