W0187

Crystal Structures of an MHC Class II Molecule, DRA/DRB1*0401, in Complex with Peptidomimetic Inhibitors. Amy L. Swain, David R. Bolin, Robert Crowther, Kouichi Ito, Ursula Kammlott, Gary L. Olson, Zoltan Nagy, Robert Palermo, Ramakanth Sarabu, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110

Four crystal structures of DRA/DRB1*0401 (DR4) with peptidic and peptidomimetic compounds were determined in complex with the superantigen, enterotoxin B, from S. aureus (SEB), two at 2.0 Å, and two at 2.4 Å resolution. The ligands bind to DR4 in an extended mode and specific interactions between the ligand and protein are identified and interpreted with respect to binding affinity. Dipeptide mimetics used to replace nonessential peptide bonds follow the geometry of a standard peptide.

The peptide binding site of DR4 is characterized and molecular contacts between each compound and DR4 have been identified. The specific interactions that are common to all four compounds may be exploited in the design of a drug that will bind selectively to rheumatoid arthritis-linked MHC Class II molecules. A previously unidentified space was observed within the binding cleft, that may provide potential for even greater ligand binding potency, if occupied by complementary chemical substituents.