CRYSTAL STRUCTURE OF THE MHC CLASS IB MOLECULE H2-M3 WITH FOUR DIFFERENT FORMYLATED-PEPTIDES. San Tai Shen^a, Chyung-Ru Wang^b, Kirsten Fischer Lindahl^b,c, Johann Deisenhofer^a,b, Dept. of Biochemistry^a, Howard Hughes Medical Institute^b, Dept. of Microbiology^c, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050

H2-M3 is a major histocompatibility complex (MHC) Ib molecule of mouse with a 10⁴-fold preference for binding N-formylated peptides. H2-M3 associates with [[beta]]2-microglobulin ([[beta]]2m) to present a polymorphic endogenous peptide derived from the mitochondrially encoded ND1 protein to CD⁸⁺ cytotoxic T cells. The crystal structure of H2-M3 with a bound formylated 9-mer peptide derived from rat ND1 protein was solved in our laboratory (Wang C-R et al., Cell, 70: 215-223, 1995). The overall structure of H2-M3 resembles MHC class Ia, such as HLA-A2 or H2-Kb, but the peptide-binding groove is different. The formyl group is coordinated by His-9 and a bound water molecule, and the side chain of the polymorphic residue which determines the antigen specificity of the bound peptide is buried.

To examine whether there is any conformational change in the MHC-peptide complex depending on the identity of the polymorphic residue, we intend to co-crystallize H2-M3 with each of four ND1 7-mer peptides that differ in the polymorphic residue (Ire, Ala, Val, and Thr). We have used molecular replacement to solve the crystal structures of H2-M3 bound with two of these peptides. The crystal strcuture determinations for the other two are still on progress.