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An allele-specific peptide-binding motif for the murine MHC class II molecule I-Ak has proven elusive. Here we demonstrate that the I-Ak molecule preferentially binds peptides that contain negatively charged amino acids at the primary anchor position (Asp or Glu at P1), and that I-Ak can also bind peptides with polar residues at P1 (Cys, Ser, Asn, Gin, or Thr), although with lower affinity. This preference for a negatively charged anchor residue is so pronounced that polyalanine peptides containing a single Asp can bind to I-Ak. Eight naturally processed peptides were found to use an Asp, as demonstrated by a drop in the I-Ak binding affinity of these peptides after Ala substitution. The chemical identity of the amino acid in the anchor position was also important in determining the ability of peptide-I-Ak complexes to resist denaturation on SDS-polyacrylamide gels. The P1 binding pockets of HLA-DR and H-2E …