Structure of endothelin ET B receptor-G i complex in a conformation stabilized by unique NPxxL motif

• Published in: Communications biology 2024-10, Vol.7 (1), p.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: Amino Acid Motifs; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go - chemistry; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gi-Go - ultrastructure; HEK293 Cells; Humans; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Receptor, Endothelin B - chemistry; Receptor, Endothelin B - metabolism
• ISSN: 2399-3642
• DOI: 10.1038/s42003-024-06905-z

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