Background: Family B G protein-coupled receptors (GPCRs) play an important role in
many physiological and pathophysiological processes. They are plasma-membrane proteins containing
an extracellular N-domain, an intracellular C-tail, seven transmembrane domains (TMs),
three extracellular (ELs) and three intracellular (ILs) loops.
Objective: This review aims to summarize the current structural and functional information for
family B GPCRs and their ligands, as well as, their physiological and pathophysiological role.
Methods: Α thorough search of bibliographic databases for peer-reviewed research literature was
undertaken. Moreover, molecular models of family B GPCRs were constructed and a structural
alignment of their amino acid sequences was performed to demonstrate common structural characteristics.
Results: In this review the family B GPCRs and their complexes with the receptor activity modifying
proteins (RAMPs) were classified into five groups and the important physiological and pathophysiological
role of these receptors was summarized. In addition, conserved residues of the Ndomain
and the TMs of these receptors were numbered, thus making feasible the comparison of
receptor structures and demonstrating common structural characteristics that are functionally important
for all family B receptors. Molecular models created in this study were used to discuss the
molecular mechanisms underlying ligand binding to family B GPCRs and receptor activation.
Conclusion: The findings of this review provide information about the structural-functional determinants
of family B GPCRs and their ligands, thus boosting the design of novel drugs with better
potencies and bioavailabilities, which might enrich the therapeutic armory for the treatment of a
wide spectrum of family B GPCRs-related disorders.