Figure 1. Going deep. GPCRs are high-priority targets for many indications including type 2 diabetes, depression, anxiety and osteoporosis. Hollenstein et al. have reported the first structure of an antagonist-bound class B GPCR and have shown that the antagonist-binding site in this class of receptors is much deeper than ligand-binding sites reported for class A.1 A second structure of a class B GPCR from Siu et al. extends the presence of a deep pocket to a second receptor, although there is no bound small molecule.2

(I) The relative location of the ligand-binding sites between class A and class B GPCRs is shown in the overlay. The class B binding site is occupied by a corticotropin-releasing factor receptor 1 (CRHR1; CRFR1) antagonist, and the location of an assortment of bound class A ligands, revealed in previously published structures, is indicated.

(II) Schematic representation of (I) showing the transmembrane helices embedded in the plasma membrane, with a deep pocket for the class B antagonist (red) near the intracellular plasma membrane interface and the shallow class A ligand-binding site (pink) near the extracellular interface.