(1) Liu B (2) Greenwood NF (3) Bonzanini JE (4) Motmaen A (5) Meyerberg J (6) Dao T (7) Xiang X (8) Ault R (9) Sharp J (10) Wang C (11) Visani GM (12) Vafeados DK (13) Roullier N (14) Nourmohammad A (15) Scheinberg DA (16) Garcia KC (17) Baker D

Science

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.

Author Info: (1) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (2) Department of Biochemistry

Author Info: (1) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (2) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (3) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Bioengineering Graduate Program, University of Washington, Seattle, WA, USA. (4) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Bioengineering Graduate Program, University of Washington, Seattle, WA, USA. (5) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (8) Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (9) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (10) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (11) Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA. (12) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (13) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (14) Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA. Department of Physics, University of Washington, Seattle, WA, USA. Department of Applied Mathematics, University of Washington, Seattle, WA, USA. Fred Hutchinson Cancer Center, Seattle, WA, USA. (15) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Weill Cornell Medicine, New York, NY, USA. (16) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. (17) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

Citation: Science 2025 Jul 24 389:386-391 Epub07/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40705892

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