9KDF

CryoEM structure of Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3

Summary for 9KDF

• Entry DOI: 10.2210/pdb9kdf/pdb
• EMDB information: 62274
• Descriptor: Calcineurin-fusion endothelin receptor type-B, Peptidyl-prolyl cis-trans isomerase FKBP1B, RES-701-3, ... (7 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 118434.14

Authors

Shihoya, W.,Akasaka, H.,Nureki, O. (deposition date: 2024-11-03, release date: 2025-05-07)

Primary citation

Shihoya, W.,Akasaka, H.,Jordan, P.A.,Lechner, A.,Okada, B.K.,Costa Machado da Cruz, G.,Sano, F.K.,Tanaka, T.,Kawahara, R.,Chaudhari, R.,Masamune, H.,Burk, M.J.,Nureki, O.
Structure of a lasso peptide bound ET B receptor provides insights into the mechanism of GPCR inverse agonism.
Nat Commun, 16:3446-3446, 2025

PubMed 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 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.

PubMed: 40263271
DOI: 10.1038/s41467-025-57960-x

Experimental method

ELECTRON MICROSCOPY (3.3 Å)