Cryo-EM and X-ray structures of an anti-MHC-I monoclonal antibody/H2-Kb complex reveal the basis of conformational dependence and allelic specificity

Monoclonal antibodies (mAbs) targeting MHC class I molecules, MHC-I, have been vital for various purposes such as tissue typing for transplantation, exploring immune activation, and investigating molecular structure and dynamics. In a previous study, the team examined a collection of murine mAbs against MHC-I, revealing the consistency between structural epitope identification and previous mapping studies.

Now, researchers present cryo-EM and X-ray crystal structures of a new mAb (AF6-88.5) in complex with the mouse MHC-I molecule H2-Kb.

The study focuses on the conformational epitope that is influenced by polymorphic amino acid residues in the MHC-I extracellular domains. The complex structure of the mAb and H2-Kb molecule reveals interactions between the mAb and residues in the 2, 3, and beta2m domains. Comparing the mAb/MHC-I complex to the unliganded mAb, slight adjustments of the mAb CDRH3 and CDRL3 loops are observed to accommodate the epitope surface.

This identified structurally site overlaps with what is seen by certain coreceptors and immunoevasins.

The researchers used amino acid sequence alignments and site-directed mutagenesis of H2-Kb, H2-Db, and beta2m to explain the allelic specificity. These findings underscore the impressive capability of antibodies to bind conformationally defined epitopes with exceptional precision and highlight the role of MHC-I polymorphisms in antigenicity.