9DL1

Crystal Structure of HLA-A*02:01/NY-ESO-1 (SLLMWITQV) and a target specific TRACeR-I

Summary for 9DL1

• Entry DOI: 10.2210/pdb9dl1/pdb
• Descriptor: TRACeR-I, MHC class I antigen, A-2 alpha chain, Beta-2-microglobulin, ... (6 entities in total)
• Functional Keywords: major histocompatibility complex i(mhc), immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 8
• Total formula weight: 122489.18

Authors

Mallik, L.,Du, H.,Huang, P.,Sgourakis, N.G. (deposition date: 2024-09-10, release date: 2024-11-20, Last modification date: 2025-10-29)

Primary citation

Du, H.,Mallik, L.,Hwang, D.,Sun, Y.,Kaku, C.,Hoces, D.,Sun, S.M.,Ghinnagow, R.,Carro, S.D.,Phan, H.A.T.,Gupta, S.,Blackson, W.,Lee, H.,Choe, C.A.,Dersh, D.,Liu, J.,Bell, B.,Yang, H.,Papadaki, G.F.,Young, M.C.,Zhou, E.,El Nesr, G.,Goli, K.D.,Eisenlohr, L.C.,Minn, A.J.,Hernandez-Lopez, R.A.,Jardine, J.G.,Sgourakis, N.G.,Huang, P.S.
Targeting peptide antigens using a multiallelic MHC I-binding system.
Nat.Biotechnol., 43:1683-1693, 2025

PubMed Abstract: Identifying highly specific T cell receptors (TCRs) or antibodies against epitopic peptides presented by class I major histocompatibility complex (MHC I) proteins remains a bottleneck in the development of targeted therapeutics. Here, we introduce targeted recognition of antigen-MHC complex reporter for MHC I (TRACeR-I), a generalizable platform for targeting peptides on polymorphic HLA-A*, HLA-B* and HLA-C* allotypes while overcoming the cross-reactivity challenges of TCRs. Our TRACeR-MHC I co-crystal structure reveals a unique antigen recognition mechanism, with TRACeR forming extensive contacts across the entire peptide length to confer single-residue specificity at the accessible positions. We demonstrate rapid screening of TRACeR-I against a panel of disease-relevant HLAs with peptides derived from human viruses (human immunodeficiency virus, Epstein-Barr virus and severe acute respiratory syndrome coronavirus 2), and oncoproteins (Kirsten rat sarcoma virus, paired-like homeobox 2b and New York esophageal squamous cell carcinoma 1). TRACeR-based bispecific T cell engagers and chimeric antigen receptor T cells exhibit on-target killing of tumor cells with high efficacy in the low nanomolar range. Our platform empowers the development of broadly applicable MHC I-targeting molecules for research, diagnostic and therapeutic applications.

PubMed: 39672954
DOI: 10.1038/s41587-024-02505-8

Experimental method

X-RAY DIFFRACTION (2.3 Å)