6igk
Crystal Structure of human ETB receptor in complex with Endothelin-3
Structural highlights
DiseaseEDNRB_HUMAN Hirschsprung disease;Waardenburg-Shah syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Defects in EDNRB are associated with Waardenburg syndrome 2, with ocular albinism, autosomal recessive: A disorder characterized by the association of features typical of Waardenburg syndrome type 2 with ocular albinism. Patients manifest reduced visual acuity, albinotic fundus, deafness, hypomelanosis.[1] FunctionEDNRB_HUMAN Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.[2] Publication Abstract from PubMedEndothelin receptors (ET(A) and ET(B)) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ET(B)-selective signalling induces vasorelaxation, and thus selective ET(B) agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ET(B) receptor in complex with ET(B)-selective agonist, endothelin-3 and an ET(B)-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(B). Crystal structures of human ET(B) receptor provide mechanistic insight into receptor activation and partial activation.,Shihoya W, Izume T, Inoue A, Yamashita K, Kadji FMN, Hirata K, Aoki J, Nishizawa T, Nureki O Nat Commun. 2018 Nov 9;9(1):4711. doi: 10.1038/s41467-018-07094-0. PMID:30413709[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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