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Structure paper

TitleStructure of a lasso peptide bound ET receptor provides insights into the mechanism of GPCR inverse agonism.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 3446, Year 2025
Publish dateApr 22, 2025
AuthorsWataru Shihoya / Hiroaki Akasaka / Peter A Jordan / Anna Lechner / Bethany K Okada / Gabriella Costa Machado da Cruz / Fumiya K Sano / Tatsuki Tanaka / Ryo Kawahara / Rajan Chaudhari / Hiroko Masamune / Mark J Burk / Osamu Nureki /
PubMed AbstractLasso 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 ...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 type B receptor (ET), which is implicated in challenging cancers with poor immunotherapy responsiveness. The Streptomyces-derived lasso peptide, RES-701-3, is a selective inhibitor for ET 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 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 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.
External linksNat Commun / PubMed:40263271 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.5 Å
Structure data

EMDB-62272: Consensus map of Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-62273: focused on refinement endothelin receptor type-B of Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
Method: EM (single particle) / Resolution: 3.5 Å

62274

9kdf

EMDB-62274, PDB-9kdf:
CryoEM structure of Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
Method: EM (single particle) / Resolution: 3.3 Å

62275

9kdg

EMDB-62275, PDB-9kdg:
CryoEM structure of Calcineurin-fusion Human endothelin receptor type-B in the ligand-free form
Method: EM (single particle) / Resolution: 3.33 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-FE:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-FK5:
8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN / medication*YM

Source
  • homo sapiens (human)
  • streptomyces venezuelae (bacteria)
  • Mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR

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