Fig. 6

Receptor activation by ET-3 and partial activation by IRL1620. Schematic representations of receptor activation by ET-3 and partial activation by IRL1620. TM6, TM7, and H8 are highlighted. The residues involved in the signal transduction (N1.50, D2.50, F6.44, W6.48, and N7.45) are represented with sticks. Hydrogen bonds are indicated by black dashed lines. Arrows indicate the conformational changes in TM6 and TM7 upon ET-3 and IRL1620 binding. In the K-8794-bound structure (left), a water-mediated hydrogen bonding network among D147^2.50, W336^6.48, and N378^7.45 stabilizes the inactive conformation of the receptor. ET-3 binding disrupts this network and propagates the structural change of the transmission switch comprising F332^6.44 and W336^6.48 (middle), leading to the outward movement of TM6 upon G-protein coupling. In the IRL1620-bound structure (right), the water-mediated hydrogen-binding network is preserved, thus preventing the outward movement of TM6 upon G-protein coupling