6IGK

Crystal Structure of human ETB receptor in complex with Endothelin-3

Summary for 6IGK

• Entry DOI: 10.2210/pdb6igk/pdb
• Descriptor: Endothelin receptor type B,Endolysin,Endothelin receptor type B, Endothelin-3, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (5 entities in total)
• Functional Keywords: alpha helical, signaling protein-protein binding complex, signaling protein/protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 63077.43

Authors

Shihoya, W.,Izume, T.,Inoue, A.,Yamashita, K.,Kadji, F.M.N.,Hirata, K.,Aoki, J.,Nishizawa, T.,Nureki, O. (deposition date: 2018-09-25, release date: 2018-11-21, Last modification date: 2024-10-23)

Primary citation

Shihoya, W.,Izume, T.,Inoue, A.,Yamashita, K.,Kadji, F.M.N.,Hirata, K.,Aoki, J.,Nishizawa, T.,Nureki, O.
Crystal structures of human ETBreceptor provide mechanistic insight into receptor activation and partial activation.
Nat Commun, 9:4711-4711, 2018

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

PubMed: 30413709
DOI: 10.1038/s41467-018-07094-0

Experimental method

X-RAY DIFFRACTION (2 Å)