Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif
Abstract Endothelin type B receptor (ETBR) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ETBR activation by the endogenous peptide hormones endothelin (ET)−1–3 stimulates several signaling pathways, includin...
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Nature Portfolio
2024-10-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-06905-z |
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| author | Kazutoshi Tani Saori Maki-Yonekura Ryo Kanno Tatsuki Negami Tasuku Hamaguchi Malgorzata Hall Akira Mizoguchi Bruno M. Humbel Tohru Terada Koji Yonekura Tomoko Doi |
| author_facet | Kazutoshi Tani Saori Maki-Yonekura Ryo Kanno Tatsuki Negami Tasuku Hamaguchi Malgorzata Hall Akira Mizoguchi Bruno M. Humbel Tohru Terada Koji Yonekura Tomoko Doi |
| author_sort | Kazutoshi Tani |
| collection | DOAJ |
| description | Abstract Endothelin type B receptor (ETBR) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ETBR activation by the endogenous peptide hormones endothelin (ET)−1–3 stimulates several signaling pathways, including Gs, Gi/o, Gq/11, G12/13, and β-arrestin. Although the conserved NPxxY motif in transmembrane helix 7 (TM7) is important during GPCR activation, ETBR possesses the lesser known NPxxL motif. In this study, we present the cryo-EM structure of the ETBR–Gi complex, complemented by MD simulations and functional studies. These investigations reveal an unusual movement of TM7 to the intracellular side during ETBR activation and the essential roles of the diverse NPxxL motif in stabilizing the active conformation of ETBR and organizing the assembly of the binding pocket for the α5 helix of Gi protein. These findings enhance our understanding of the interactions between GPCRs and G proteins, thereby advancing the development of therapeutic strategies. |
| format | Article |
| id | doaj-art-e309a935434d4d2dbb4055a9ce1118fc |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-e309a935434d4d2dbb4055a9ce1118fc2025-08-20T02:17:46ZengNature PortfolioCommunications Biology2399-36422024-10-017111310.1038/s42003-024-06905-zStructure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motifKazutoshi Tani0Saori Maki-Yonekura1Ryo Kanno2Tatsuki Negami3Tasuku Hamaguchi4Malgorzata Hall5Akira Mizoguchi6Bruno M. Humbel7Tohru Terada8Koji Yonekura9Tomoko Doi10Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, TsukubaRIKEN SPring-8 Center, 1-1-1, Kouto, SayoScientific Imaging Section, Research Support Division, Okinawa Institute of Science and Technology Graduate University (OIST), 1919-1, Tancha, Onna-son, Kunigami-gunDepartment of Biotechnology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-kuRIKEN SPring-8 Center, 1-1-1, Kouto, SayoScientific Imaging Section, Research Support Division, Okinawa Institute of Science and Technology Graduate University (OIST), 1919-1, Tancha, Onna-son, Kunigami-gunGraduate School of Medicine, Mie University, 2–174 Edobashi TsuProvost Office, Okinawa Institute of Science and Technology Graduate University (OIST), 1919-1, Tancha, Onna-son, Kunigami-gunDepartment of Biotechnology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-kuRIKEN SPring-8 Center, 1-1-1, Kouto, SayoGraduate School of Science, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-kuAbstract Endothelin type B receptor (ETBR) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ETBR activation by the endogenous peptide hormones endothelin (ET)−1–3 stimulates several signaling pathways, including Gs, Gi/o, Gq/11, G12/13, and β-arrestin. Although the conserved NPxxY motif in transmembrane helix 7 (TM7) is important during GPCR activation, ETBR possesses the lesser known NPxxL motif. In this study, we present the cryo-EM structure of the ETBR–Gi complex, complemented by MD simulations and functional studies. These investigations reveal an unusual movement of TM7 to the intracellular side during ETBR activation and the essential roles of the diverse NPxxL motif in stabilizing the active conformation of ETBR and organizing the assembly of the binding pocket for the α5 helix of Gi protein. These findings enhance our understanding of the interactions between GPCRs and G proteins, thereby advancing the development of therapeutic strategies.https://doi.org/10.1038/s42003-024-06905-z |
| spellingShingle | Kazutoshi Tani Saori Maki-Yonekura Ryo Kanno Tatsuki Negami Tasuku Hamaguchi Malgorzata Hall Akira Mizoguchi Bruno M. Humbel Tohru Terada Koji Yonekura Tomoko Doi Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif Communications Biology |
| title | Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif |
| title_full | Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif |
| title_fullStr | Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif |
| title_full_unstemmed | Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif |
| title_short | Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif |
| title_sort | structure of endothelin etb receptor gi complex in a conformation stabilized by unique npxxl motif |
| url | https://doi.org/10.1038/s42003-024-06905-z |
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