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


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.

SUBMITTER: Shihoya W 

PROVIDER: S-EPMC6226434 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Crystal structures of human ET<sub>B</sub> receptor provide mechanistic insight into receptor activation and partial activation.

Shihoya Wataru W   Izume Tamaki T   Inoue Asuka A   Yamashita Keitaro K   Kadji Francois Marie Ngako FMN   Hirata Kunio K   Aoki Junken J   Nishizawa Tomohiro T   Nureki Osamu O  

Nature communications 20181109 1


Endothelin receptors (ET<sub>A</sub> and ET<sub>B</sub>) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ET<sub>B</sub>-selective signalling induces vasorelaxation, and thus selective ET<sub>B</sub> agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ET<sub>B</sub> receptor in complex with ET<sub>B</sub>-selective agonist, endothelin-3 and an  ...[more]

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