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Structure of a lasso peptide bound ETB receptor provides insights into the mechanism of GPCR inverse agonism
Open accessPreprint — published as 10.1038/s41467-025-57960-x · Paper page
Abstract
Lasso peptides exhibit a unique lariat-like knotted structure imparting exceptional stability and thus show promise as therapeutic agents that target cell-surface receptors. One such receptor is the human endothelin ET B receptor, which is implicated in challenging cancers with poor immunotherapy responsiveness. The Streptomyces-derived lasso peptide, RES-701-3, is a selective inhibitor for ET B and a compelling candidate for therapeutic development. However, meager production from a genetically recalcitrant host has limited further structure-activity relationship studies of this potent inhibitor. Here, we report cryo-electron microscopy structures of ET B receptor in both its apo form and complex with RES-701-3, facilitated by a calcineurin-fusion strategy. Hydrophobic interactions between RES-701-3 and the transmembrane region of the receptor, especially involving two tryptophan residues, play a crucial role in RES-701-3 binding. Furthermore, RES-701-3 prevents conformational changes associated with G-protein coupling, explaining its inverse agonist activity. A comparative analysis with other lasso peptides and their target proteins highlights the potential of lasso peptides as precise drug candidates for G-protein-coupled receptors. This structural insight into RES-701-3 binding to ET B receptor offers valuable information for the development of novel therapeutics targeting this receptor and provides a broader understanding of lasso peptide interactions with human cell-surface receptors.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Nureki, O., Shihoya, W., Akasaka, H., Sano, F., Tanaka, T., Kawahara, R., Jordan, P., Lechner, A., Okada, B., Cruz, G. M. D., Chaudhari, R., Masamune, H., & BurK, M.
- Affiliations
- The University of Tokyo (JP)
- Lassogen Inc.
- Eurofins (United States) (US)
- Corresponding author
- Nureki, Osamu
- Shihoya, Wataru
- BurK, Mark
- ORCID
- Venue
- Nature Communications
- Published
- 2024-02-06
- Volume
- 16
- Issue
- 1
- Pages
- 3446-3446
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12015262
- OpenAlex
- W4409681433
- Cited by
- 8
- References
- 1
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development (JP23ama121002, JP233fa627001, JP23ama121012)
- Ministry of Education, Culture, Sports, Science and Technology (21H05037)
- Kao Foundation for Arts and Sciences
- Ono Medical Research Foundation
- Japan Society for the Promotion of Science (22H02751, 21H05037, 23KJ0491, 22K19371)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- lasso peptides, endothelin B receptor, G protein coupling, ligand-receptor interactions, hydrophobic interactions, tryptophan residues, transmembrane domain, cancer immunotherapy
- MeSH terms
- Humans, Models, Molecular, Peptides, Protein Binding, Protein Conformation, Structure-Activity Relationship, Cryoelectron Microscopy, Receptors, G-Protein-Coupled, Receptor, Endothelin B, Drug Inverse Agonism, HEK293 Cells
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