TY - JOUR
T1 - Crystal structures of human ET B receptor provide mechanistic insight into receptor activation and partial activation
AU - Shihoya, Wataru
AU - Izume, Tamaki
AU - Inoue, Asuka
AU - Yamashita, Keitaro
AU - Kadji, Francois Marie Ngako
AU - Hirata, Kunio
AU - Aoki, Junken
AU - Nishizawa, Tomohiro
AU - Nureki, Osamu
N1 - Funding Information:
We thank the members of the Nureki lab and the beamline staff at BL32XU of SPring-8 (Sayo, Japan) for technical assistance during data collection. The diffraction experiments were performed at SPring-8 BL32XU (proposal 2016A2527). This work was supported by JSPS KAKENHI grants 16H06294 (O.N.), 17J30010 (W.S.), 30809421 (W.S.), 15H06862 (K.Y.), 17H05000 (T.N.), and 17K08264 (A.I.), and the Core Research for Evolutional Science, PRESTO from the Japan Science and Technology (JST) Technology Program; the Platform for Drug Discovery, Information, and Structural Life Science from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and the Japan Agency for Medical Research and Development (AMED) grants the PRIME JP17gm5910013 (A.I.) and the LEAP JP17gm0010004 (A.I. and J.A.), and the National Institute of Biomedical Innovation.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Endothelin 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 .
AB - Endothelin 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 .
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U2 - 10.1038/s41467-018-07094-0
DO - 10.1038/s41467-018-07094-0
M3 - Article
C2 - 30413709
AN - SCOPUS:85056287259
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4711
ER -