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monkeys have evolved MHC-encoded class I allomorphs such as Mamu-B\u2217098 that are capable of binding N-myristoylated short lipopeptides rather than conventional long peptides; however, it remains unknown whether such antigen-binding molecules exist in other species, including humans. We herein demonstrate that human leukocyte antigen (HLA)-A\u221724:02 and HLA-C\u221714:02 proteins, which are known to bind conventional long peptides, also have the potential to bind N-myristoylated short lipopeptides. These HLA class I molecules shared a serine at position 9 (Ser9) with Mamu-B\u2217098, in contrast to most MHC class I molecules that harbor a larger amino acid residue, such as tyrosine, at this position. High resolution X-ray crystallographic analyses of lipopeptide-bound HLA-A\u221724:02 and HLA-C\u221714:02 complexes indicated that Ser9 was at the bottom of the B pocket with its small hydroxymethyl side chain directed away from the B-pocket cavity, thereby contributing to the formation of a deep hydrophobic cavity suitable for accommodating the long-chain fatty acid moiety of lipopeptide ligands. Upon peptide binding, however, we found the hydrogen-bond network involving Ser9 was reorganized, and the remodeled B pocket was able to capture the second amino acid residue (P2) of peptide ligands. Apart from the B pocket, virtually no marked alterations were observed for the A and F pockets upon peptide and lipopeptide binding. Thus, we concluded that the structural flexibility of the large B pocket of HLA-A\u22172402 and HLA-C\u22171402 primarily accounted for their previously unrecognized capacity to bind such chemically distinct ligands as conventional peptides and N-myristoylated lipopeptides.","bibjson":{"author":[{"initials":null,"lastname":null,"name":"Asa, M."},{"initials":null,"lastname":null,"name":"Morita, D."},{"initials":null,"lastname":null,"name":"Kuroha, J."},{"initials":null,"lastname":null,"name":"Mizutani, T."},{"initials":null,"lastname":null,"name":"Mori, N."},{"initials":null,"lastname":null,"name":"Mikami, B."},{"initials":null,"lastname":null,"name":"Sugita, M."}],"identifier":[{"id":"10.1016/j.jbc.2022.102100","type":"doi"},{"id":"35667438","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":null,"name":""},"pages":["102100-102100"],"title":"Crystal structures of N-myristoylated lipopeptide-bound HLA class I complexes indicate reorganization of B-pocket architecture upon ligand binding.","type":"article","url":"https://www.sciencedirect.com/science/article/abs/pii/S0021925822005415","volume":["298"],"year":[2022]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.56","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/7wj3"},"rcsb":{"url":"https://www.rcsb.org/structure/7wj3"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-C*14:02 binding \"GAAL\" at 1.56Å resolution","unique_chain_count":3}}