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T cell receptors (TCRs) can crossreact with both self- and foreign- major histocompatibility complex (MHC) proteins in an enigmatic phenomenon termed alloreactivity. Here we present the 2.35 A structure of the 2C TCR complexed with its foreign ligand H-2L(d)-QL9. Surprisingly, we find that this TCR utilizes a different strategy to engage the foreign pMHC in comparison to the manner in which it recognizes a self ligand H-2K(b)-dEV8. 2C engages both shared and polymorphic residues on L(d) and K(b), as well as the unrelated QL9 and dEV8 peptide antigens, in unique pair-wise contacts, resulting in greater structural complementarity with the L(d)-QL9 complex. In the structure of an engineered, high-affinity 2C TCR variant bound to H-2L(d)-QL9, the \"wild-type\" TCR-MHC binding orientation persists despite modified TCR-CDR3alpha interactions with peptide. Thus, a single TCR recognizes two globally similar, but distinct ligands by divergent mechanisms, indicating that receptor-ligand crossreactivity can occur in the absence of molecular mimicry.","bibjson":{"author":[{"initials":"LA","lastname":"Colf","name":"Colf LA"},{"initials":"AJ","lastname":"Bankovich","name":"Bankovich AJ"},{"initials":"NA","lastname":"Hanick","name":"Hanick NA"},{"initials":"NA","lastname":"Bowerman","name":"Bowerman NA"},{"initials":"LL","lastname":"Jones","name":"Jones LL"},{"initials":"DM","lastname":"Kranz","name":"Kranz DM"},{"initials":"KC","lastname":"Garcia","name":"Garcia KC"}],"identifier":[{"id":"10.1016/j.cell.2007.01.048","type":"doi"},{"id":"17418792","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Cell","name":""},"pages":["135-46"],"title":"How a single T cell receptor recognizes both self and foreign MHC.","type":"article","url":"https://www.sciencedirect.com/science/article/abs/pii/S0092867407003133","volume":["129"],"year":[2007]},"in_pmc":"N","in_pmce":"N","open_access":"N"},"resolution":"2.50","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/2e7l"},"rcsb":{"url":"https://www.rcsb.org/structure/2e7l"},"stcrdab":{"url":"http://opig.stats.ox.ac.uk/webapps/stcrdab/StrViewer?pdb=2e7l"}},"species":{"common_name":"Mouse","match_type":"histo:assign_species","scientific_name":"Mus musculus","slug":"mus_musculus"},"tcr":{"alpha":{"chains":["A"],"subgroup":"TRAV9"},"beta":{"chains":["D"],"subgroup":"TRBV13"},"mhc_type":"class_i","pdb_code":"2e7l"},"title":"Truncated H2-Ld presenting \"QLSPFPFDL\" to Alpha/Beta T cell receptor at 2.50Å resolution","unique_chain_count":4}}