April 24, 2025
The University of Tokyo
Keio University
Key Points of the Announcement
◆ Using cryo-electron microscopy, we have revealed how the lasso peptide "RES-701," with its unique lasso-like structure, binds to the ETB receptor, an important cell surface protein in the human body.
◆ We found that this peptide fits snugly into a specific pocket within the ETB receptor, thereby inhibiting the receptor's normal intracellular signal transduction.
◆ This suggests the potential for applying the high selectivity and stability of lasso peptides to novel drug discovery strategies targeting the ETB receptor.
A research group led by Associate Professor Wataru Shihoya of The Sakaguchi Laboratory (Signal Quest), Keio University School of Medicine (formerly an assistant professor at the Department of Biological Sciences, Graduate School of Science, The University of Tokyo), Professor Osamu Nureki of the Department of Biological Sciences, Graduate School of Science, The University of Tokyo, and Lassogen Inc. has determined the binding structure of the lasso peptide RES-701 to the endothelin B (ETB) receptor, a type of G protein-coupled receptor (GPCR) on the cell surface, using cryo-electron microscopy (cryo-EM) single-particle analysis. The ETB receptor, a GPCR, is known to regulate vascular function and is involved in cancer angiogenesis and immune responses, making it a promising therapeutic target for intractable cancers for which the development of therapeutic drugs is eagerly awaited. However, previous development efforts have failed to produce small molecule compounds with sufficient modulatory activity and selectivity. RES-701, a lasso peptide, shows higher selectivity for the ETB receptor than existing drugs and has shown promise as an inverse agonist, but elucidating its mechanism of action on the ETB receptor remained a challenge for its future application in drug discovery.
In this study, by applying the calcineurin fusion method, the researchers successfully determined the structure of the ETB receptor bound to RES-701, which had previously been difficult to achieve, and visualized how the peptide binds to a specific hydrophobic pocket inside the receptor. This binding was found to inhibit the conformational changes required for the interaction between the G protein and the receptor, thereby realizing its inverse agonist activity.
This achievement paves the way for the development of pharmaceuticals based on lasso peptides targeting the ETB receptor and is expected to have applications for various diseases, particularly in the treatment of immunotherapy-resistant cancers.
For the full press release, please see below.