X-ray structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation

Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ETB-selective signaling induces vasorelaxation, and thus selective ETB agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. The effectiveness of a highly ETB-selective endothelin analogue, IRL1620, has been investigated in clinical trials. Here, we report the crystal structures of human ETB receptor in complex with ETB-selective agonists, endohelin-3 and IRL1620. The 2.0 Å-resolution structure of the endothelin-3-bound receptor revealed that the disruption of water-mediated interactions between W6.48 and D2.50, which are highly conserved among class A GPCRs, is critical for receptor activation. These hydrogen-bonding interactions are partially preserved in the IRL1620-bound structure, and a functional analysis revealed the partial agonistic effect of IRL1620. The current findings clarify the detailed molecular mechanism for the coupling between the orthosteric pocket and the G-protein binding, and the partial agonistic effect of IRL1620, thus paving the way for the design of improved agonistic drugs targeting ETB.