Crystal Structure of HLA-DR2 (DRA*0101, DRB1*1501) Complexed with a Peptide from Human Myelin Basic Protein

doi:10.1084/jem.188.8.1511

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J. Exp. Med., Volume 188, Number 8, October 19, 1998 1511-1520

Crystal Structure of HLA-DR2 (DRA0101, DRB11501) Complexed with a Peptide from Human Myelin Basic Protein

By Kathrine J. Smith,^* Jason Pyrdol,^§ Laurent Gauthier,^§ Don C. Wiley,^* and Kai W. Wucherpfennig^§

From the ^* Department of Molecular Medicine, Children's Hospital, Boston, Massachusetts 02115; the Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138; the ^§ Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115

Susceptibility to multiple sclerosis is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 (DRB1*1501)haplotype. The structure of HLA-DR2 was determined with a boundpeptide from human myelin basic protein (MBP) that is immunodominantfor human MBP-specific T cells. Residues of MBP peptide that areimportant for T cell receptor recognition are prominent, solventexposed residues in the crystal structure. A distinguishing featureof the HLA-DR2 peptide binding site is a large, primarily hydrophobicP4 pocket that accommodates a phenylalanine of the MBP peptide.The necessary space for this aromatic side chain is created byan alanine at the polymorphic DR $beta$ 71 position. These featuresmake the P4 pocket of HLA-DR2 distinct from DR molecules associatedwith other autoimmune diseases.

Key words: HLA-DR2; crystal structure; myelin basic protein; multiple sclerosis; autoimmunity

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