9MIN

Structure of a designed minibinder to NYESO1-A*02:01

Summary for 9MIN

• Entry DOI: 10.2210/pdb9min/pdb
• Descriptor: HLA class I antigen, Beta-2-microglobulin, Cancer/testis antigen 1, ... (7 entities in total)
• Functional Keywords: complex, immune system, de novo protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 148052.32

Authors

Jude, K.M.,Householder, K.D. (deposition date: 2024-12-13, release date: 2025-08-06)

Primary citation

Householder, K.D.,Xiang, X.,Jude, K.M.,Deng, A.,Obenaus, M.,Zhao, Y.,Wilson, S.C.,Chen, X.,Wang, N.,Garcia, K.C.
De novo design and structure of a peptide-centric TCR mimic binding module.
Science, 389:375-379, 2025

PubMed Abstract: T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-major histocompatibility complex (pMHC) in cancer immunotherapy. In this study, we designed a de novo α-helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by human leukocyte antigen (HLA)-A*02, achieving high on-target specificity with nanomolar affinity (dissociation constant = 9.5 nM). The structure of the TCRm-pMHC complex at 2.05-Å resolution revealed a rigid TCR-like docking mode with an unusual degree of focus on the up-facing NY-ESO-1 side chains, suggesting the potential for reduced off-target reactivity. Indeed, a structure-informed in silico screen of 14,363 HLA-A*02 peptides correctly predicted two off-target peptides, yet our TCRm maintained peptide selectivity and cytotoxicity as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused α-helical TCR mimics.

PubMed: 40705894
DOI: 10.1126/science.adv3813

Experimental method

X-RAY DIFFRACTION (2.05 Å)