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TitleA general system for targeting MHC class II-antigen complex via a single adaptable loop.
Journal, issue, pagesNat Biotechnol, Vol. 43, Issue 10, Page 1673-1682, Year 2025
Publish dateDec 13, 2024
AuthorsHaotian Du / Jingjia Liu / Kevin M Jude / Xinbo Yang / Ying Li / Braxton Bell / Hongli Yang / Audrey Kassardjian / Wyatt Blackson / Ali Mobedi / Udit Parekh / R Andres Parra Sperberg / Jean-Philippe Julien / Elizabeth D Mellins / K Christopher Garcia / Po-Ssu Huang /
PubMed AbstractMajor 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 ...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.
External linksNat Biotechnol / PubMed:39672953 / PubMed Central
MethodsEM (single particle)
Resolution2.28 Å
Structure data

43499

8vsj

EMDB-43499, PDB-8vsj:
Engineered peptide-specific binder in complex with HLA-DR1/CLIP
Method: EM (single particle) / Resolution: 2.28 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • metamycoplasma arthritidis (bacteria)
KeywordsIMMUNE SYSTEM / complex / engineered protein

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