Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif
Endothelin type B receptor (ET<sub>B</sub>R) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ET<sub>B</sub>R activation by the endogenous peptide hormones endothelin (ET)-1-3 stimulates several signaling pathways, including G<sub>s</sub>, G<sub>i/o</sub>, G<sub>q/11</sub>, G<sub>12/13</sub>, and β-arrestin. Although the conserved NPxxY motif in transmembrane helix 7 (TM7) is important during GPCR activation, ET<sub>B</sub>R possesses the lesser known NPxxL motif. In this study, we present the cryo-EM structure of the ET<sub>B</sub>R-G<sub>i</sub> complex, complemented by MD simulations and functional studies. These investigations reveal an unusual movement of TM7 to the intracellular side during ET<sub>B</sub>R activation and the essential roles of the diverse NPxxL motif in stabilizing the active conformation of ET<sub>B</sub>R and organizing the assembly of the binding pocket for the α5 helix of G<sub>i</sub> protein. These findings enhance our understanding of the interactions between GPCRs and G proteins, thereby advancing the development of therapeutic strategies.
Authors
- Bruno M. Humbel (ORCID: https://orcid.org/0000-0002-7095-1368)
- Akira Mizoguchi (ORCID: https://orcid.org/0000-0002-7492-2791)
- Kazutoshi Tani (ORCID: https://orcid.org/0000-0003-4835-154X)
- Tasuku Hamaguchi (ORCID: https://orcid.org/0000-0003-0876-7700)
- Koji Yonekura (ORCID: https://orcid.org/0000-0001-5520-4391)
- Malgorzata Hall
- Tatsuki Negami
- Saori Maki-Yonekura (ORCID: https://orcid.org/0000-0002-8295-8794)
- Tohru Terada (ORCID: https://orcid.org/0000-0002-7091-0646)
- Tomoko Doi (ORCID: https://orcid.org/0000-0002-6568-4576)
- Ryo Kanno
Institutions
- Okinawa Institute of Science and Technology Graduate University (JP)
- University of Tsukuba (JP)
- Mie University (JP)
- Tohoku University (JP)
- Kyoto University (JP)
- Juntendo University (JP)
- SPring-8 (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1038/s42003-024-06905-z
- Citations
- 8
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Japan Agency for Medical Research and Development
- Cabinet Office, Government of Japan
- Okinawa Institute of Science and Technology Graduate University
- University of Tsukuba
- Japan Society for the Promotion of Science
- JST-Mirai Program