Abstract
Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ETB-selective signalling induces vasorelaxation, and thus selective ETB agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ETB receptor in complex with ETB-selective agonist, endothelin-3 and an ETB-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 ETB.
Highlights
Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation
We first investigated the biochemical activities of ET-3 and IRL1620 for the human endothelin receptors, by TGFα shedding (G-protein activation, the Gq and the G12 families) and β-arrestin recruitment assays
The EC50 and Emax values of ET-3 for the ETB receptor were similar to those of ET-1 in both assays, while the EC50 value for ETA was about 5-fold lower (Fig. 1a, b, and Table 1, Table 2). These data indicate that ET-3 functions as a full agonist for the endothelin receptors, with moderate ETB-selectivity
Summary
Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. Since the ETB-selective signal improves blood flow, IRL1620 could be utilized for the improved efficacy of anti-cancer drugs by increasing the efficiency of drug delivery, as shown in rat models of prostate and breast cancer[18,19,20,21]. This strategy can be applied to radiotherapy in the treatment of solid tumours, as the radiation-induced reduction in the tumour volume was enhanced by IRL162022. The stimulation of the ETB receptor by IRL1620 reduces the cognitive impairment induced by beta amyloid (1-40), a pathological hallmark of Alzheimer’s disease, in rat experiments[24,25]
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