Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 Å resolution

Abstract

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, α_1 onto α_2 and α_3 onto β_2m, 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 α_1 and α_2 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 β_2m and the HLA heavy chain presumably involved in β_2m 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 β_2m in stabilizing permissible peptide complexes during folding and assembly is presented.

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