8VSJ

Engineered peptide-specific binder in complex with HLA-DR1/CLIP

Summary for 8VSJ

• Entry DOI: 10.2210/pdb8vsj/pdb
• EMDB information: 43499
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen DR beta chain, Superantigen, ... (7 entities in total)
• Functional Keywords: complex, engineered protein, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 108783.39

Authors

Jude, K.M.,Yang, X.,Du, H.,Kassardjian, A.,Julien, J.-P.,Huang, P.,Garcia, K.C. (deposition date: 2024-01-24, release date: 2024-10-02, Last modification date: 2025-02-19)

Primary citation

Du, H.,Liu, J.,Jude, K.M.,Yang, X.,Li, Y.,Bell, B.,Yang, H.,Kassardjian, A.,Blackson, W.,Mobedi, A.,Parekh, U.,Parra Sperberg, R.A.,Julien, J.P.,Mellins, E.D.,Garcia, K.C.,Huang, P.S.
A general system for targeting MHC class II-antigen complex via a single adaptable loop.
Nat.Biotechnol., 2024

PubMed Abstract: Major histocompatibility complex class II (MHCII) bound to a peptide antigen mediates interactions between CD4 T cells and antigen-presenting cells. Targeting peptide-MHCII with T cell antigen receptors (TCRs) and TCR-like antibodies has shown promise for autoimmune diseases and microbiome tolerance. To develop a general targeting approach, we introduce targeted recognition of antigen-MHC complex reporter for MHCII (TRACeR-II) for the rapid development of peptide-specific MHCII binders. TRACeR-II binders have a small helical bundle scaffold and use a single loop to recognize peptide-MHCII, which offers versatility and enables structural modeling of the interactions to target MHCII antigens. We demonstrate rapid generation of TRACeR-II binders to multiple molecules with affinities in the low-nanomolar to low-micromolar range, comparable to best-in-class TCRs and antibodies. Through computational protein design, we created specific binding sequences in silico from only the sequence of a severe acute respiratory syndrome coronavirus 2 peptide. TRACeR-II provides a straightforward approach to target antigen-MHCII without relying on combinatorial selection on complementarity-determining region loops.

PubMed: 39672953
DOI: 10.1038/s41587-024-02466-y

Experimental method

ELECTRON MICROSCOPY (2.28 Å)