Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation

Wataru Shihoya, Tamaki Izume, Asuka Inoue, Keitaro Yamashita, Francois Marie Ngako Kadji, Kunio Hirata, Junken Aoki, Tomohiro Nishizawa () and Osamu Nureki ()
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Wataru Shihoya: The University of Tokyo
Tamaki Izume: The University of Tokyo
Asuka Inoue: Tohoku University
Keitaro Yamashita: The University of Tokyo
Francois Marie Ngako Kadji: Tohoku University
Kunio Hirata: RIKEN SPring-8 Center
Junken Aoki: Tohoku University
Tomohiro Nishizawa: The University of Tokyo
Osamu Nureki: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07094-0

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