Structural and functional insights into the juxtamembranous amino-terminal tail and extracellular loop regions of...

Class B guanine nucleotide-binding protein GPCRs share heptahelical topology and signalling via coupling with heterotrimeric G proteins typical of the entire superfamily of GPCRs. However, they also exhibit substantial structural differences from the more extensively studied class A GPCRs. Even their helical bundle region, most conserved across the superfamily, is predicted to differ from that of class A GPCRs. Much is now known about the conserved structure of the amino-terminal domain of class B GPCRs, coming from isolated NMR and crystal structures, but the orientation of that domain relative to the helical bundle is unknown, and even less is understood about the conformations of the juxtamembranous amino-terminal tail or of the extracellular loops linking the transmembrane segments. We now review what is known about the structure and function of these regions of class B GPCRs. This comes from indirect analysis of structure-function relationships elucidated by mutagenesis and/or ligand modification and from the more direct analysis of spatial approximation coming from photoaffinity labelling and cysteine trapping studies. Also reviewed are the limited studies of structure of some of these regions. No dominant theme was recognized for the structures or functional roles of distinct regions of these juxtamembranous portions of the class B GPCRs. Therefore, it is likely that a variety of molecular strategies can be engaged for docking of agonist ligands and for initiation of conformational changes in these receptors that would be expected to converge to a common molecular mechanism for activation of intracellular signalling cascades.