Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region

Abstract

Class A G-protein-coupled receptors (GPCRs) are a large family of membrane proteins that mediate a wide variety of physiological functions, including vision, neurotransmission and immune responses. They are the targets of nearly one-third of all prescribed medicinal drugs such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins. Structural rearrangements of residue contacts in the transmembrane domain serve as 'activation pathways' that connect the ligand-binding pocket to the G-protein-coupling region within the receptor. In order to investigate the similarities in activation pathways across class A GPCRs, we analysed 27 GPCRs from diverse subgroups for which structures of active, inactive or both states were available. Here we show that, despite the diversity in activation pathways between receptors, the pathways converge near the G-protein-coupling region. This convergence is mediated by a highly conserved structural rearrangement of residue contacts between transmembrane helices 3, 6 and 7 that releases G-protein-contacting residues. The convergence of activation pathways may explain how the activation steps initiated by diverse ligands enable GPCRs to bind a common repertoire of G proteins.

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

“…This structural similarity near the G protein coupling sites reflects a convergence of activation pathways, which has been highlighted in family A GPCRs 43 , and enables this large family of receptors to bind and get activated by very diverse ligands, but signal intracellularly via a small common repertoire of G proteins. While further work is needed to provide a detailed picture of activation pathways in different GPCR classes, we anticipate that the application of the rapidly evolving cryo-EM technologies will transform structural studies of these challenging proteins.…”

Ligand Modulation of Sidechain Dynamics in a Wild-Type Human GPCR

“…The residue I238 6.40 is situated further toward the G protein binding site at a critical region for GPCR activation, where it packs against TM7 and undergoes significant outward movement in the transition to the active conformation ( Figure 7C). I238 6.40 is also one helical turn on TM6 above L235 6.37 , which participates in a conserved microswitch between inactive and active conformations for multiple GPCRs (Venkatakrishnan et al, 2016). I292 is present at the linker between TM7 and Helix 8, where it packs against Y288 7.53 of the highly conserved NPXXY motif (Katritch et al, 2013) ( Figure 7D).…”

“…The importance of repacking of sidechains from TM3, TM5, and TM6 beneath the ligand binding pocket, known as the 'conserved core triad,' was identified by comparison of structures of b 2 AR (Rosenbaum et al, 2011;Rasmussen et al, 2011a) and the m-opioid receptor . Further down the TM bundle, an activated microswitch near the site of G protein binding has been found to represent a common feature of GPCRs that have been crystallized in both active and inactive conformations (Venkatakrishnan et al, 2016). A working hypothesis for GPCR activation is that a set of loosely coupled microswitches connecting the orthosteric pocket and G protein binding site are activated by agonists in a non-concerted fashion, and stabilizing subsets of these rearrangements can lead to alternate overall conformations that have different signaling properties.…”

Clinically Approved Ion Channel Inhibitors Close Gates for Hepatitis C Virus and Open Doors for Drug Repurposing in Infectious Viral Diseases

“…The H 1 histamine receptor and dopamine receptors all belong to family A, the rhodopsin-like GPCRs (33; http:// www.gpcrdb.org). Receptors of family A GPCRs usually bind their ligands within a transmembrane pocket involving contact residues within several GPCR transmembrane helices (27,28). Ligand binding triggers conformational changes that relocate helices and unmask previously inaccessible binding sites for G proteins (28,34).…”

“…GPCRs coordinate a large spectrum of physiological reactions by receiving signaling input from the extracellular milieu and relaying this information into the cell through interactions with G proteins, thus permitting adequate responses to hormones, neurotransmitters, and environmental stimuli (26). GPCRs homo-or heteroligomerize constitutively or upon ligand binding (27), and they are the targets of almost one-third of prescribed drugs, including beta blockers and antipsychotics (28,29). Accumulating structural information about GPCRs bound to ligands or antagonists is now disclosing the architecture of drug binding sites within GPCR transmembrane helices and guides modeling approaches to identify compounds that selectively target specific GPCRs (30-32).…”