Prostaglandin E receptor EP4, a class A G protein-coupled receptor (GPCR), is a common drug target in various disorders, such as acute decompensated heart failure and ulcerative colitis. Here, we report the cryoelectron microscopy (cryo-EM) structure of the EP4-heterotrimeric G protein (Gs) complex with the endogenous ligand at a global resolution of 3.3 Å. In this structure, compared with that in the inactive EP4 structure, the sixth transmembrane domain is shifted outward on the intracellular side, although the shift is smaller than that in other class A GPCRs bound to Gs. Instead, the C-terminal helix of Gs is inserted toward TM2 of EP4, and the conserved C-terminal hook structure formsthe extended state. These structural features are formed by the conserved residues in prostanoid receptors (Phe542.39 and Trp3277.51). These findings may be important for the thorough understanding of the G protein-binding mechanism of EP4 and other prostanoid receptors. Nojima and Fujita et al. determined the cryo-EM structure of prostaglandin E receptor EP4 bound to the heterotrimeric G protein and the endogenous ligand PGE2. The structure reveals the novel binding mode between GPCRs and Gs, which provides us the information for the structure-based activation mechanism of prostanoid receptors.
All Science Journal Classification (ASJC) codes
- Structural Biology
- Molecular Biology