Crystal structures of human ET(B) receptor provide mechanistic insight into receptor activation and partial activation.

Endothelin receptors (ET(A) and ET(B)) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ET(B)-selective signalling induces vasorelaxation, and thus selective ET(B) agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ET(B) receptor in complex with ET(B)-selective agonist, endothelin-3 and an ET(B)-selective endothelin analogue IRL1620. The structure of the endothelin-3-bound receptor reveals that the disruption of water-mediated interactions between W6.48 and D2.50 is critical for receptor activation, while these hydrogen-bonding interactions are partially preserved in the IRL1620-bound structure. Consistently, functional analysis reveals 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 ET(B).