8ESH

Structure of chimeric HLA-A*02:01 bound to CMV peptide

Summary for 8ESH

• Entry DOI: 10.2210/pdb8esh/pdb
• Descriptor: HLA-A*02:01, Beta-2-microglobulin, CMV peptide, ... (4 entities in total)
• Functional Keywords: major histocompatibility complex (mhc), immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 44599.42

Authors

Florio, T.J.,Ani, O.,Young, M.C.,Mallik, L.,Sgourakis, N.G. (deposition date: 2022-10-14, release date: 2023-01-25, Last modification date: 2023-10-25)

Primary citation

Papadaki, G.F.,Ani, O.,Florio, T.J.,Young, M.C.,Danon, J.N.,Sun, Y.,Dersh, D.,Sgourakis, N.G.
Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules.
Front Immunol, 14:1116906-1116906, 2023

PubMed Abstract: Major Histocompatibility Complex class I (MHC-I) molecules display self, viral or aberrant epitopic peptides to T cell receptors (TCRs), which employ interactions between complementarity-determining regions with both peptide and MHC-I heavy chain 'framework' residues to recognize specific Human Leucocyte Antigens (HLAs). The highly polymorphic nature of the HLA peptide-binding groove suggests a malleability of interactions within a common structural scaffold. Here, using structural data from peptide:MHC-I and pMHC:TCR structures, we first identify residues important for peptide and/or TCR binding. We then outline a fixed-backbone computational design approach for engineering synthetic molecules that combine peptide binding and TCR recognition surfaces from existing HLA allotypes. X-ray crystallography demonstrates that chimeric molecules bridging divergent HLA alleles can bind selected peptide antigens in a specified backbone conformation. Finally, tetramer staining and biophysical binding experiments using chimeric pMHC-I molecules presenting established antigens further demonstrate the requirement of TCR recognition on interactions with HLA framework residues, as opposed to interactions with peptide-centric Chimeric Antigen Receptors (CARs). Our results underscore a novel, structure-guided platform for developing synthetic HLA molecules with desired properties as screening probes for peptide-centric interactions with TCRs and other therapeutic modalities.

PubMed: 36761745
DOI: 10.3389/fimmu.2023.1116906

Experimental method

X-RAY DIFFRACTION (2.72 Å)