9NNF

Cryo-EM structure of a de-novo designed binder NY1-B04 in complex with HLA-A*02:01 and NY-ESO-1-derived peptide SLLMWITQC

Summary for 9NNF

• Entry DOI: 10.2210/pdb9nnf/pdb
• EMDB information: 49573
• Descriptor: De-novo designed binder NY1-B04, HLA class I histocompatibility antigen, A alpha chain, Beta-2-microglobulin, ... (4 entities in total)
• Functional Keywords: de novo-designed pmhc binders, hla, immune system
• Biological source: synthetic construct; More
• Total number of polymer chains: 4
• Total formula weight: 59979.28

Authors

Gharpure, A.,Fernandez-Quintero, M.L.,Ward, A.B. (deposition date: 2025-03-05, release date: 2025-07-23, Last modification date: 2025-08-06)

Primary citation

Johansen, K.H.,Wolff, D.S.,Scapolo, B.,Fernandez-Quintero, M.L.,Risager Christensen, C.,Loeffler, J.R.,Rivera-de-Torre, E.,Overath, M.D.,Kjaergaard Munk, K.,Morell, O.,Viuff, M.C.,Lacunza, I.,Damm Englund, A.T.,Due, M.,Gharpure, A.,Forli, S.,Rodriguez Pardo, C.,Tamhane, T.,Qingjie Andersen, E.,Haldrup Bjornsson, K.,Fernandes, J.S.,Voss, L.F.,Thumtecho, S.,Ward, A.B.,Ormhoj, M.,Reker Hadrup, S.,Jenkins, T.P.
De novo-designed pMHC binders facilitate T cell-mediated cytotoxicity toward cancer cells.
Science, 389:380-385, 2025

PubMed Abstract: The recognition of intracellular antigens by CD8 T cells through T cell receptors (TCRs) is central for adaptive immunity against infections and cancer. However, the identification of TCRs from patient material remains complex. We present a rapid de novo minibinder (miBd) design platform leveraging state-of-the-art generative models to engineer miBds targeting the cancer-associated peptide-bound major histocompatibility complex (pMHC) SLLMWITQC/HLA-A*02:01 (NY-ESO-1). Incorporating in silico cross-panning enabled computational prescreening of specificity, and molecular dynamics simulations allowed for improved predictability of in vitro success. We identified a high-affinity NY-ESO-1 binder and confirmed its structure using cryo-electron microscopy, which, when incorporated in a chimeric antigen receptor, induced killing of NY-ESO-1 melanoma cells. We further designed and validated binders to a neoantigen pMHC complex, RVTDESILSY/HLA-A*01:01, with unknown structure, demonstrating the potential for precision immunotherapy.

PubMed: 40705893
DOI: 10.1126/science.adv0422

Experimental method

ELECTRON MICROSCOPY (3.8 Å)