8CN6

CD59 in complex with CP-06 peptide

Summary for 8CN6

• Entry DOI: 10.2210/pdb8cn6/pdb
• Descriptor: CD59 glycoprotein, Cyclic peptide CP-06, ZINC ION, ... (4 entities in total)
• Functional Keywords: peptide bound complex, terminal complement inhibitor, lipid binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 59108.59

Authors

Bickel, J.,Ahmed, A.,Morgan, M.,Horrell, S.,El Omari, K.,Couves, E.C.,Bubeck, D.,Tate, E. (deposition date: 2023-02-22, release date: 2024-11-13, Last modification date: 2025-05-28)

Primary citation

Bickel, J.K.,Ahmed, A.I.S.,Pidd, A.B.,Morgan, R.M.,McAllister, T.E.,Horrell, S.,Couves, E.C.,Nagaraj, H.,Bartlett, E.J.,El Omari, K.,Kawamura, A.,Bubeck, D.,Tate, E.W.
Macrocyclic Peptide Probes for Immunomodulatory Protein CD59: Potent Modulators of Bacterial Toxin Activity and Antibody-Dependent Cytotoxicity.
Angew.Chem.Int.Ed.Engl., :e202422673-e202422673, 2025

PubMed Abstract: CD59 is an immunomodulatory cell surface receptor associated with human disease. Despite its importance in complement regulation and bacterial pathogenesis, CD59 remains a challenging therapeutic target. Research to date has focused on antibody or protein-based strategies. Here we present a new approach to target CD59 using macrocyclic peptides with low nanomolar affinity for CD59. Through X-ray crystallographic studies and structure-activity relationship (SAR) studies, we identify key interactions that are essential for binding and activity. We find that the macrocyclic peptide CP-06 adopts a beta-hairpin structure and binds CD59 through an intermolecular beta-sheet, mimicking protein-protein interactions of biologically relevant CD59 interaction partners. We create dimeric and lipidated macrocyclic peptide conjugates as enhanced cell-active CD59 inhibitors and show that these probes can be used to modulate both complement-mediated killing of human cells and lytic activity of bacterial virulence factors. Together, our data provide a starting point for future development of macrocyclic peptides to target CD59 activity in diverse cellular contexts.

PubMed: 40272315
DOI: 10.1002/anie.202422673

Experimental method

X-RAY DIFFRACTION (2.43 Å)