Crystal structures of human ET<sub>B</sub> receptor provide mechanistic insight into receptor activation and partial activation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30413709.
- Also identified by DOI 10.1038/s41467-018-07094-0 and PMC identifier 6226434.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 ET<sub>B</sub>-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<sub>B</sub>.
Medical subject headings
- Receptor, Endothelin B