Fig. 5

Comparison of the K8794, ET-3, and IRL1620-bound structures. a–c Comparison of the K-8794-bound inactive (PDB 5X93), IRL1620-bound partially active, and ET-3-bound active ET_B structures, coloured turquoise, orange, and orange-red, respectively. The ET_B receptors and agonist peptides are shown as ribbon models, viewed from the intracellular side (a), the extracellular side (b), and the membrane plane (c). The cytoplasmic cavity for the G-protein binding is still hindered by the inwardly-oriented TM6 in the ET-3 and IRL1620-bound receptors, representing the inactive conformations. This is consistent with the notion that the fully active conformation is only stabilized when the G-protein is bound, as shown in the previous nuclear magnetic resonance (NMR) and double electron–electron resonance (DEER) spectroscopy study³⁸. d–f Superimposition of the ET_B structures bound to K-8794 and ET-3 (d), K-8794 and IRL1620 (e), and K-8794, IRL1620, and ET-3 (f), focused on the intermembrane parts. The receptors are shown as ribbons, and the side chains of N119^1.50, D147^2.50, F332^6.44, W336^6.48, and N378^7.45 are shown as sticks with transparent surface representations. Waters are shown as red spheres. The dashed lines show hydrogen bonds coloured in the respective structures. The arrows show the structural changes on ligand binding