ISSN:
0948-5023
Keywords:
Major Histocompatibility Complex proteins
;
Insulin-dependent diabetes mellitus
;
Peptide docking
;
Molecular modeling
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Molecular modeling techniques were used to generate structures of several HLA-DQ proteins associated with insulin-dependent diabetes mellitus (IDDM). A peptide fragment from glutamic acid decarboxylase (GAD), a known IDDM autoantigen, binds to certain HLA-DQ molecules positively associated with IDDM. Modeling studies were used to explore possible binding interactions between this GAD peptide and several HLA-DQ molecules. Based on the characterization of anchor pockets in the HLA-DQ binding groove and of peptide side chains, a novel binding mode was proposed. This binding mode predicts the GAD peptide is positioned in the binding groove in the direction opposite the orientation observed for class I proteins and the class II DR1, DR3, and I-Ek proteins. Peptide docking exercises were performed to construct models of the HLA-DQ/peptide complexes, and the resulting models have been used to design peptide binding experiments to test this “reverse-orientation” binding mode. A variety of experimental results are consistent with the proposed model and suggest that some peptide ligands of class II molecules may bind in a reversed orientation within the binding groove.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s0089460020205
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