Current understanding of the structure and function of family B GPCRs to design novel drugs

Abstract

Family B of G-protein-coupled receptors (GPCRs) and their ligands play a central role in a number of homeostatic mechanisms in the endocrine, gastrointestinal, skeletal, immune, cardiovascular and central nervous systems. Alterations in family B GPCR-regulated homeostatic mechanisms may cause a variety of potentially life-threatening conditions, signifying the necessity to develop novel ligands targeting these receptors. Obtaining structural and functional information on family B GPCRs will accelerate the development of novel drugs to target these receptors. Family B GPCRs are proteins that span the plasma membrane seven times, thus forming seven transmembrane domains (TM1-TM7) which are connected to each other by three extracellular (EL) and three intracellular (IL) loops. In addition, these receptors have a long extracellular N-domain and an intracellular C-tail. The upper parts of the TMs and ELs form the J-domain of receptors. The C-terminal region of peptides first binds to the N-domain of receptors. This 'first-step' interaction orients the N-terminal region of peptides towards the J-domain of receptors, thus resulting in a 'second-step' of ligand-receptor interaction that activates the receptor. Activation-associated structural changes of receptors are transmitted through TMs to their intracellular regions and are responsible for their interaction with the G proteins and activation of the latter, thus resulting in a biological effect. This review summarizes the current information regarding the structure and function of family B GPCRs and their physiological and pathophysiological roles.

Dimerization/oligomerization of the extracellular domain of the GLP‐1 receptor and the negative cooperativity in its ligand binding revealed by the improved NanoBiT

“…The family B GPCRs are characterized by a large and unique NTD consisting of approximately 160 amino acids . These receptor NTDs mediate the ligand recognition and binding as well as intracellular signaling for some well‐known endogenous hormones, such as secretin, parathyroid hormone, glucagon, and glucagon‐like peptide‐1 . Homo‐ and heterodimers are usually observed for the members of the family B GPCRs, where the TMs rather than their NTDs provide the primary interfaces for their dimerization .…”

“…8 These receptor NTDs mediate the ligand recognition and binding as well as intracellular signaling for some wellknown endogenous hormones, such as secretin, parathyroid hormone, glucagon, and glucagon-like peptide-1. 9,10 Homoand heterodimers are usually observed for the members of the family B GPCRs, 11 where the TMs rather than their NTDs provide the primary interfaces for their dimerization. 4,12,13 In the parathyroid hormone receptor (PTH1R), an exception among this family, NTD-mediated oligomerization has been demonstrated.…”

Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP

“…As is the case for all GPCRs, the GLP-1R consists of an extracellular N-terminal domain (N-domain), an intracellular C-terminal region, and seven TMs that are connected to each other by three extracellular loops (ELs) and also three intracellular loops (10,69). The ELs and TMs form the J-domain of receptor that binds GLP-1.…”

Capturing Peptide–GPCR Interactions and Their Dynamics

“…Secretin-like GPCRs display a generally more open, V-shaped transmembrane binding pocket compared to rhodopsin-like GPCRs. They also feature a large N-terminal extracellular domain (ECD) that importantly contributes to peptide binding [ 24 , 33 , 34 ]. Strikingly, binding modes of peptide ligands are variable even among receptors of the same phylogenetic family and are hardly generalizable, which reflects the high specificity of their physiological function.…”