PDBsum entry 1uvq

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Immunology PDB id
Protein chains
182 a.a. *
181 a.a. *
20 a.a. *
NAG ×2
Waters ×371
* Residue conservation analysis

References listed in PDB file
Key reference
Title Crystal structure of hla-Dq0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy.
Authors C.Siebold, B.E.Hansen, J.R.Wyer, K.Harlos, R.E.Esnouf, A.Svejgaard, J.I.Bell, J.L.Strominger, E.Y.Jones, L.Fugger.
Ref. Proc Natl Acad Sci U S A, 2004, 101, 1999-2004. [DOI no: 10.1073/pnas.0308458100]
PubMed id 14769912
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.
Figure 1.
Fig. 1. 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 1 is shown in blue chicken wire. The peptide is depicted in ball-and-stick colored as in A and viewed through the 1-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 C 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 46 to 55 and 85 to 91 show significant main chain and side chain conformational changes between the two MHC class II structures. The C positions of these residues in DQ0602 are indicated by spheres (blue, -chain; magenta, -chain). The concerted conformational changes impact on the P1 pocket (see text) and on the heterodimer interface. In particular, residue 48 changes from leucine in DQ0302 to tryptophan in DQ0602, and the side chain of Trp-48 (shown in blue sticks) is reoriented to form a tight, hydrophobic interaction at the interface with the 2 domain.
Figure 3.
Fig. 3. 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.
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