TY - JOUR
T1 - Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500
AU - Nagiri, Chisae
AU - Shihoya, Wataru
AU - Inoue, Asuka
AU - Kadji, Francois Marie Ngako
AU - Aoki, Junken
AU - Nureki, Osamu
N1 - Funding Information:
The diffraction experiments were performed at SPring-8 BL32XU (proposal 2017A2527 and 2017B2578). The authors thank the beamline staff at BL32XU of SPring-8 (Sayo, Japan) for technical assistance during data collection. The authors also thank Kouki Kawakami, Takeaki Shibata, and Ayumi Inoue (Tohoku University, Japan) for technical assistance in the characterization of the L3.43Q-mutant ETB and ETA receptors. The authors also thank K. Yamashita for the assistance of the PDB deposition and uploading the raw data. This work was supported by grants from the Platform for Drug Discovery, Informatics and Structural Life Science by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), JSPS KAKENHI grants 16H06294 (O.N.), 17J30010 (W.S.), 30809421 (W.S.), 17K08264 (A.I.), 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:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Endothelin receptors (ETA and ETB) are G-protein-coupled receptors activated by endothelin-1 and are involved in blood pressure regulation. IRL2500 is a peptide-mimetic of the C-terminal tripeptide of endothelin-1, and has been characterized as a potent ETB-selective antagonist, which has preventive effects against brain edema. Here, we report the crystal structure of the human ETB receptor in complex with IRL2500 at 2.7 Å-resolution. The structure revealed the different binding modes between IRL2500 and endothelin-1, and provides structural insights into its ETB-selectivity. Notably, the biphenyl group of IRL2500 penetrates into the transmembrane core proximal to D2.50, thus stabilizing the inactive conformation. Using the newly-established constitutively active mutant, we clearly demonstrate that IRL2500 functions as an inverse agonist for the ETB receptor. The current findings will expand the chemical space of ETR antagonists and facilitate the design of inverse agonists for other class A GPCRs.
AB - Endothelin receptors (ETA and ETB) are G-protein-coupled receptors activated by endothelin-1 and are involved in blood pressure regulation. IRL2500 is a peptide-mimetic of the C-terminal tripeptide of endothelin-1, and has been characterized as a potent ETB-selective antagonist, which has preventive effects against brain edema. Here, we report the crystal structure of the human ETB receptor in complex with IRL2500 at 2.7 Å-resolution. The structure revealed the different binding modes between IRL2500 and endothelin-1, and provides structural insights into its ETB-selectivity. Notably, the biphenyl group of IRL2500 penetrates into the transmembrane core proximal to D2.50, thus stabilizing the inactive conformation. Using the newly-established constitutively active mutant, we clearly demonstrate that IRL2500 functions as an inverse agonist for the ETB receptor. The current findings will expand the chemical space of ETR antagonists and facilitate the design of inverse agonists for other class A GPCRs.
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U2 - 10.1038/s42003-019-0482-7
DO - 10.1038/s42003-019-0482-7
M3 - Article
C2 - 31263780
AN - SCOPUS:85071170750
SN - 2399-3642
VL - 2
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 236
ER -