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

Hormones (Athens). 2018 Mar;17(1):45-59. doi: 10.1007/s42000-018-0009-5. Epub 2018 Apr 19.


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.

Keywords: Antagonists; Binding; Family B GPCRs; Ligands; Physiological/pathophysiological role; Receptor activation; Signaling; Structure.

Publication types

  • Review

MeSH terms

  • Drug Design*
  • Humans
  • Ligands
  • Protein Binding
  • Protein Conformation
  • Receptors, G-Protein-Coupled / chemistry*


  • Ligands
  • Receptors, G-Protein-Coupled