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The association of HLA class I heavy chains with ß2-microglobulin (ß2m) changes their antigenic profile. As a result, Abs react with either ß2m-free or ß2m-associated HLA class I heavy chains. An exception to this rule is the mAb TP25.99, which reacts with both ß2m-associated and ß2m-free HLA class I heavy chains. The reactivity with ß2m-associated HLA class I heavy chains is mediated by a conformational determinant expressed on all HLA-A, -B, and -C Ags. This determinant has been mapped to amino acid residues 194–198 in the α3 domain. The reactivity with ß2m-free HLA class I heavy chains is mediated by a linear determinant expressed on all HLA-B Ags except the HLA-B73 allospecificity and on <50% of HLA-A allospecificities. The latter determinant has been mapped to amino acid residues 239–242, 245, and 246 in the α3 domain. The conformational and the linear determinants share several structural features, but have no homology in their amino acid sequence. mAb TP25.99 represents the first example of a mAb recognizing two distinct and spatially distant determinants on a protein. The structural homology of a linear and a conformational determinant on an antigenic entity provides a molecular mechanism for the sharing of specificity by B and TCRs.