Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif

• Published in: Communications biology 2024-10, Vol.7 (1), p.1303-13, Article 1303
• Main Authors: Tani, Kazutoshi, Maki-Yonekura, Saori, Kanno, Ryo, Negami, Tatsuki, Hamaguchi, Tasuku, Hall, Malgorzata, Mizoguchi, Akira, Humbel, Bruno M., Terada, Tohru, Yonekura, Koji, Doi, Tomoko
• Format: Article
• Language: English
• Subjects: 101/28; 631/45/535; 631/535/1258/1259; 82/83; Arrestin; Biomedical and Life Sciences; Blood pressure; Endothelins; G protein-coupled receptors; Homeostasis; Life Sciences; Peptide hormones; Protein structure; Proteins; Therapeutic targets
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06905-z

Endothelin type B receptor (ET B R) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ET B R activation by the endogenous peptide hormones endothelin (ET)−1–3 stimulates several signaling pathways, including G s , G i/o , G q/11 , G 12/13 , and β-arrestin. Although the conserved NPxxY motif in transmembrane helix 7 (TM7) is important during GPCR activation, ET B R possesses the lesser known NPxxL motif. In this study, we present the cryo-EM structure of the ET B R–G i complex, complemented by MD simulations and functional studies. These investigations reveal an unusual movement of TM7 to the intracellular side during ET B R activation and the essential roles of the diverse NPxxL motif in stabilizing the active conformation of ET B R and organizing the assembly of the binding pocket for the α5 helix of G i protein. These findings enhance our understanding of the interactions between GPCRs and G proteins, thereby advancing the development of therapeutic strategies. Tani et al. present the cryo-EM structure of the endothelin type B receptor (ETBR) in complex with the Gi protein, emphasizing the movements of transmembrane helix 7 during ETBR activation. The study underscores the crucial role of the NPxxL motif in stabilizing the receptor's active state and organizing the Gi protein binding site, enhancing our understanding of GPCR activation and aiding therapeutic development.