The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/10/1511/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 8, October 19, 1998 1511-1520

Articles

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

Kathrine J. Smith*,{ddagger}, Jason Pyrdol§, Laurent Gauthier§, Don C. Wiley*,{ddagger}, and Kai W. Wucherpfennig§,||

From the * Department of Molecular Medicine, Children's Hospital, Boston, Massachusetts 02115; the {ddagger} 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 bound peptide from human myelin basic protein (MBP) that is immunodominant for human MBP-specific T cells. Residues of MBP peptide that are important for T cell receptor recognition are prominent, solvent exposed residues in the crystal structure. A distinguishing feature of the HLA-DR2 peptide binding site is a large, primarily hydrophobic P4 pocket that accommodates a phenylalanine of the MBP peptide. The necessary space for this aromatic side chain is created by an alanine at the polymorphic DRβ 71 position. These features make the P4 pocket of HLA-DR2 distinct from DR molecules associated with other autoimmune diseases.

Key Words: HLA-DR2 • crystal structure • myelin basic protein • multiple sclerosis • autoimmunity

Address correspondence to Kai W. Wucherpfennig, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: 617-632-3086; Fax: 617-632-2662; E-mail: wucherpf{at}mbcrr.harvard.edu

We have benefited from the continuing collaboration with Dr. Jack L. Strominger on aspects of MHC biology. K.W. Wucherpfennig would like to thank Dr. Jack L. Strominger for encouragement and support during earlier stages of the project.

Coordinates will be deposited in the Protein Data Bank (Brookhaven National Laboratory, Upton, NY) and are available before their release by E-mail (ksmith{at}rascal.med.harvard.edu).

Abbreviations used: HA, hemagglutinin; MBP, myelin basic protein; MS, multiple sclerosis.


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