Specificity pockets for the side chains of peptide antigens in HLA-Aw68.
We have determined the structure of a second human histocompatibility glycoprotein, HLA-Aw68, by X-ray crystallography and refined it to a resolution of 2.6 A. Overall, the structure is extremely similar to that of HLA-A2 (refs 1, 2; and M.A.S. et al., manuscript in preparation), although the 11 amino-acid substitutions at polymorphic residues in the antigen-binding cleft alter the detailed shape and electrostatic charge of that site. A prominent negatively charged pocket within the cleft extends underneath the alpha-helix of the alpha 1-domain, providing a potential subsite for recognizing a positively charged side chain or peptide N terminus. Uninterpreted electron density, presumably representing an unknown 'antigen(s)', which seems to be different from that seen in the HLA-A2 structure, occupies the cleft and extends into the negatively charged pocket in HLA-Aw68. The structures of HLA-Aw68 and HLA-A2 demonstrate how polymorphism creates and alters subsites (pockets) positioned to bind peptide side chains, thereby suggesting the structural basis for allelic specificity in foreign antigen binding.
Garrett
T P
TP
Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, Massachusetts 02138.
Saper
M A
MA
Bjorkman
P J
PJ
Strominger
J L
JL
Wiley
D C
DC
D000595:Amino Acid Sequence; D000941:Antigens / Q000378:metabolism*; D001665:Binding Sites; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D014961:X-Ray Diffraction
D000941:Antigens; D015234:HLA-A Antigens; C053029:HLA-A*68 antigen; D015789:HLA-A2 Antigen