1. Structural studies of Class I MHC antigens. The structural analysis of naturally occurring population variants of Class I HLA antigens HLA-A2, -B7, -B27 and -B8, will be carried out in order to define functional sites in these molecules. 2. Structural studies of Class II MHC antigens. The separation of subsets of Class II HLA antigens (HLA-Dr, DQ and DP) at the protein level is essential for full characterization and, in particular, to investigate several novel features of the SQ and DP subsets, as well as to obtain materials for use in crystallization and in functional studies. The structures of the DQ2 Alpha and Beta alleles in normal individuals and in patients with coeliac disease will be investigated in order to establish whether or not the linkage of this autoimmune disease to DQ1 is associated with a particular 'disease allele'. The structures of two DRw6Beta chains in two DRw6 cells (WT46 and WT52) will be examined to ascertain if genetic exchange between DRBeta alleles may have led to the generation of these cell lines. 3. The interaction of Class I and Class II MHC antigens with human T cell specific proteins T4 and T8. Several techniques will be employed to examine the possibility that a functionally important protein-protein interaction can occur between these molecules. 4. The crystal structures of immunologically important molecules. The crystal structure of HLA-A2 is advancing rapidly and will be completed. Crystallization of a secreted form of HLA-A2 will also be attempted. Attempts to obtain, crystallize and examine the crystal structure of a soluble form of HLA-DR1 and of both water soluble and detergent soluble forms of the T cell specific protein T8 will be made. Finally, the use of genetic manipulation to obtain soluble forms of immunologically important molecules for crystallographic studies will be explored.
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