Fig. 5.

HLA-G may bind to LIR-1 (ILT-2) with enhanced affinity and undergo disulfide-bond-mediated dimerization. (A) Comparative analysis of the candidate ILT-2 binding site on the α3 domain of HLA-G (purple) and the equivalent binding site on HLA-A2 (yellow). (B) Model of the HLA-G dimer, looking down onto the antigen-binding cleft; peptides are in red (A protomer, light gray) and pink (B protomer, dark gray). The dimerization site is mediated via an intermolecular Cys-42–Cys-42 disulfide, indicating that the protomers within the dimer cannot adopt a side-by-side arrangement. However, a head-to-tail HLA-G dimer would satisfy the requirements for a Cys-42-mediated dimer, in which the loops containing the Cys-42 would clasp onto each other. In this plausible configuration, intermolecular interactions mediated via the β2M domains are possible. LIR-1 has been solved in complex with HLA-A2 (Protein Data Bank ID code 1P7Q), in which the LIR-1 binding site onto the α3 domain of the hc was mapped. Given the similarities between HLA-G and HLA-A2, the molecular organization of the HLA-G/ILT2 complex can be postulated in this HLA-G dimeric arrangement (ILT2 in blue and cyan).