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The MHC class II molecule DQ0602 confers strong susceptibility to narcolepsy but dominant protection against type 1 diabetes. The crystal structure of DQ0602 reveals the molecular features underlying these contrasting genetic properties. Structural comparisons to homologous DQ molecules with differential disease associations highlight a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of an expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role.

Original publication

DOI

10.1073/pnas.0308458100

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

09/02/2004

Volume

101

Pages

1999 - 2004

Addresses

Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.

Keywords

Humans, Narcolepsy, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Membrane Glycoproteins, HLA-DQ Antigens, Crystallography, X-Ray, Binding Sites, Amino Acid Sequence, Protein Conformation, Protein Binding, Structure-Activity Relationship, Polymorphism, Genetic, Alleles, Models, Molecular, HLA-DQ beta-Chains