Role of the polymorphic residues in HLA-DR molecules in allele-specific binding of peptide ligands.
Analysis of peptide binding to a set of HLA-DR alleles has allowed the proteins to be segregated into functional subsets, depending on the amino acids at positions 57 and 86 of the beta-chain. DR proteins with glycine at 86 beta and aspartic acid at 57 beta bound a simplified peptide with significantly lower IC50 values than alleles that did not have this combination of amino acids. The size of the amino acid at 86 beta seemed to modify the steric requirements for the single most important side chain of the peptide. Within each of the four subgroups, other polymorphic amino acids define allele-specific binding requirements. These were explored by analyzing the ability of eight different DR alleles to bind 13 known T cell determinants. The side chains in the peptides that seemed to be responsible for allele specificity were determined by correlating their common structural features with complementary polymorphic residues in the binding site. The importance of these residues was tested by incorporating them into a polyalanine backbone, and was confirmed by the ability of these residues to transfer allele specificity to these simplified analogues. Even though polymorphic contacts affected peptide affinity, the majority of the free energy of binding in all cases arose from interactions with the peptide backbone and the single hydrophobic amino acid at the third position. These constraints seem to orient all peptides in a similar location, forcing them to adopt a closely related conformation in the binding site. The corresponding side chain in each peptide contacts the same pocket in the binding site, regardless of the allele. This apparent similarity should allow any DR allele to be analyzed by extrapolation from the DR1 crystal structure.
Marshall
K W
KW
ImmuLogic Pharmaceutical Corporation, Palo Alto, CA 94304.
Liu
A F
AF
Canales
J
J
Perahia
B
B
Jorgensen
B
B
Gantzos
R D
RD
Aguilar
B
B
Devaux
B
B
Rothbard
J B
JB
D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D013329:Structure-Activity Relationship
D006684:HLA-DR Antigens; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; C019529:polyalanine