The crystal structure of DQ0602–hypocretin. (A) The solvent-accessible surface of the DQ0602 peptide binding groove is colored by electrostatic potential (blue, positive charge; red, negative charge) viewed onto the TCR recognition surface. The residues of the peptide are shown as ball-and-stick in atomic coloring (blue, nitrogen; red, oxygen; yellow, peptide carbon). The major pockets within the groove are labeled in the standard MHC class II nomenclature. (B) A composite omit map contoured at 1σ is shown in blue chicken wire. The peptide is depicted in ball-and-stick colored as in A and viewed through the β1-helix. (C) A superposition of the peptides from the DQ0602–hypocretin and DQ0302–insulinB structures. The peptides are shown with atomic coloring as in A except for the insulinB peptide carbon atoms (green). The view is as in B, and the residues are labeled in the standard MHC class II nomenclature. (D) Superposition of the DQ0602 and DQ0302 peptide binding grooves. The Cα traces for DQ0602 (gray) and for DQ0302 (green) are viewed as in A. The well ordered residues of the hypocretin peptide and linker are shown with atomic coloring (peptide coloring as in A; orange, linker carbon). Residues 46α to 55α and 85β to 91β show significant main chain and side chain conformational changes between the two MHC class II structures. The Cα positions of these residues in DQ0602 are indicated by spheres (blue, α-chain; magenta, β-chain). The concerted conformational changes impact on the P1 pocket (see text) and on the heterodimer interface. In particular, residue 48α changes from leucine in DQ0302 to tryptophan in DQ0602, and the side chain of Trp-48α (shown in blue sticks) is reoriented to form a tight, hydrophobic interaction at the interface with the β2 domain.

The P6 pocket and T1D. (A) Stereoview of a superposition of selected residues from DQ0602–hypocretin with the equivalent residues from DQ0302–insulinB. Main chain is shown as coil, and selected residue side chains are depicted as ball-and-stick (yellow, hypocretin peptide; green, DQ0602; magenta, DQ0302–insulinB). The P6 residue in both the hypocretin and insulinB peptides is valine. (B) Stereoview of the DQ0602–hypocretin complex as in A. The volume bound by the blue chicken wire shows the increase in the P6 pocket size of DQ0602 when compared with DQ0302. The volume was defined by the program volumes as local difference between the solvent-accessible surfaces of the two binding grooves after superposition.

The P4 pocket and narcolepsy. (A) Stereoview of selected residues contributing to the P4 pocket of DQ0602. Main chain and selected residue side chains are depicted as sticks and color-coded as in Fig. 3. (B) Superposition with polymorphic residues modeled for DQ06011 colored in magenta.

Disease-associated polymorphisms. (A) Disease-associated residues as highlighted by sequence alignment of selected DQ chains. Residues associated with T1D are red, and those associated with narcolepsy are green. The binding groove pockets to which these residues contribute are indicated. (B) The DQ0602 binding groove is shown in Cα trace, with the hypocretin peptide depicted in the standard format (Fig. 1) and the Cα positions of residues highlighted in A indicated by spheres (red, T1D; green, narcolepsy).

The P9 pocket and T1D. (A) Stereoview of selected residues contributing to the P9 pocket of DQ0602. Main chain and selected residue side chains are depicted as sticks and color-coded as in Fig. 3. A tightly bound water molecule is shown as a red sphere, and hydrogen bonds are represented as orange dashed lines. (B) Stereoview of the equivalent residues at the P9 pocket of the DQ0302–insulinB complex. The color coding is as in A but with green substituted by magenta. (C) Superposition of the residues shown in A and B. The color coding is conserved, with the exception of the peptide in the DQ0302–insulinB complex (magenta, carbon). For clarity, hydrogen bonds and water are omitted.