Unravelling class B GPCRs

Structural studies of the transmembrane domain (TMD) of G protein-coupled receptors (GPCRs), which can largely be classified as class A, class B or class C, have mainly focused on class A receptors. Two papers now present crystal structures of the TMD of class B GPCRs. Hollenstein et al. solved the structure of the TMD of human corticotropin-releasing factor 1 receptor (CRF1R), in complex with a small-molecule agonist, at 3 Å resolution. Siu et al. solved the structure of the TMD of the glucagon receptor, the amino-terminal domain of which was replaced by a thermally stabilized protein, at 3.4 Å. The authors compared the position of the seven transmembrane helices in their structures with the position of these in representative class A GPCRs. The positioning of helices TM6 and TM7 at the extracellular face of class A and class B GPCRs differed; this changes the relative position of helices TM6 to TM5 and TM1 to TM7 in class B structures and widens what is thought to be the peptide binding cavity. Differences were also observed between the CRF1R and glucagon receptor structures, in particular in the upper segments of TM6 and TM7. These structures provide a model for all class B GPCRs and reveal several features of these receptors against which novel drugs could be designed.