REFINED STRUCTURE OF THE HUMAN HISTOCOMPATIBILITY ANTIGEN HLA-A2 AT 2.6A RESOLUTION

The three-dimensional structure of the human histocompatibility antigen HLA-A2 was determined at 3.5 Å resolution by a combination of isomorphous replacement and iterative real-space averaging of two crystal forms. The monoclinic crystal form has now been refined by least-squares methods to an R-factor of 0.169 for data from 6 to 2.6 Å resolution. A superposition of the structurally similar domains found in the heterodimer, α1onto α2 and α3onto β2m, as well as the latter pair onto the ancestrally related immunoglobulin constant domain, reveals that differences are mainly in the turn regions. Structural features of the α1 and α2 domains, such as conserved salt-bridges that contribute to stability, specific loops that form contacts with other domains, and the antigen-binding groove formed from two adjacent helical regions on top of an eight-stranded β-sheet, are analyzed. The interfaces between the domains, especially those between β2m and the HLA heavy chain presumably involved in β2m exchange and heterodimer assembly, are described in detail. A detailed examination of the binding groove confirms that the solvent-accessible amino acid side-chains that are most polymorphic in mouse and human alleles fill up the central and widest portion of the binding groove, while conserved side-chains are clustered at the narrower ends of the groove. Six pockets or sub-sites in the antigen-binding groove, of diverse shape and composition, appear suited for binding side-chains from antigenic peptides. Three pockets contain predominantly non-polar atoms; but others, especially those at the extreme ends of the groove, have clusters of polar atoms in close proximity to the "extra" electron density in the binding site. A possible role for β2m in stabilizing permissible peptide complexes during folding and assembly is presented. © 1991.