{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Papadaki GF"],"funding":["National Institute of Allergy and Infectious Diseases","NIDDK NIH HHS","National Institute of Diabetes and Digestive and Kidney Diseases","NIAID NIH HHS","National Institute of General Medical Sciences","NIGMS NIH HHS"],"pagination":["1116906"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9905809"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14"],"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, <i>in vitro</i> 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."],"journal":["Frontiers in immunology"],"pubmed_title":["Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules."],"pmcid":["PMC9905809"],"funding_grant_id":["U01 DK112217","R01 AI143997","R35 GM125034"],"pubmed_authors":["Danon JN","Papadaki GF","Dersh D","Florio TJ","Ani O","Sun Y","Sgourakis NG","Young MC"],"additional_accession":[]},"is_claimable":false,"name":"Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules.","description":"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, <i>in vitro</i> 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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023","modification":"2026-05-28T12:47:06.338Z","creation":"2025-04-05T19:42:23.67Z"},"accession":"S-EPMC9905809","cross_references":{"pubmed":["36761745"],"doi":["10.3389/fimmu.2023.1116906"]}}