Design of high-specificity binders for peptide–MHC-I complexes Journal Article
| Authors: | Liu, B.; Greenwood, N. F.; Bonzanini, J. E.; Motmaen, A.; Meyerberg, J.; Dao, T.; Xiang, X.; Ault, R.; Sharp, J.; Wang, C.; Visani, G. M.; Vafeados, D. K.; Roullier, N.; Nourmohammad, A.; Scheinberg, D. A.; Garcia, K. C.; Baker, D. |
| Article Title: | Design of high-specificity binders for peptide–MHC-I complexes |
| Abstract: | Class I major histocompatibility complex (MHC-I) molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance. Proteins that recognize peptide–MHC-I (pMHCI) complexes with specificity for diseased cells could have considerable therapeutic utility. Specificity requires recognition of outward-facing amino acid residues within the disease-associated peptide as well as avoidance of extensive contacts with ubiquitously expressed MHC. We used RFdiffusion to design pMHCI-binding proteins that make extensive contacts with the peptide and identified specific binders for 11 target pMHCs starting from either experimental or predicted pMHCI structures. upon incorporation into chimeric antigen receptors, designs for eight targets conferred peptide-specific T cell activation. Our approach should have broad utility for both protein- and cell-based pMHCI targeting. © 2025 Elsevier B.V., All rights reserved. |
| Keywords: | human cell; protein; peptide; t lymphocyte receptor; antigen; chimeric antigen receptor; cell therapy; amino acid; immunosurveillance; major histocompatibility complex; leukocyte antigen; t lymphocyte activation; design; fluorescence intensity; cell component; human; article; hek293t cell line; class i major histocompatibility complex |
| Journal Title: | Science |
| Volume: | 389 |
| Issue: | 6758 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2025-07-24 |
| Start Page: | 386 |
| End Page: | 391 |
| Language: | English |
| DOI: | 10.1126/science.adv0185 |
| PROVIDER: | scopus |
| PUBMED: | 40705892 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
