Universal open MHC-I molecules for rapid peptide loading and enhanced complex stability across HLA allotypes

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Class I major histocompatibility complex (MHC-I) molecules are crucial for immune response but their polymorphic nature and instability pose challenges for antigen identification and therapeutic development.
• Suboptimal peptides, metabolites, or glycolipids can further destabilize MHC-I molecules, hindering the discovery of disease-relevant antigens and antigen-specific T cell receptors (TCRs).

Conclusions:

• The engineered disulfide bond successfully stabilizes MHC-I molecules in an open, peptide-receptive conformation, overcoming intrinsic instability.
• This structure-guided approach provides a universal platform for generating stable, ready-to-load MHC-I systems applicable to diverse HLA allotypes.
• The findings offer structural and biophysical insights for designing ultra-stable, universal ligand exchange systems for immunological research and therapeutic development.