spacer Crystal structure of an immune complex at pH 6.5
Primary citation
Title Crystal Structure of the HLA-DM-HLA-DR1 Complex Defines Mechanisms for Rapid Peptide Selection.
Authors Pos, W.search; Sethi, D.K.search; Call, M.J.search; Schulze, M.S.search; Anders, A.K.search; Pyrdol, J.search; Wucherpfennig, K.W.search
Journal CELL(CAMBRIDGE,MASS.)search vol:151, pag:1557-1568 (2012), Identifiers: PubMed ID (23260142)search DOI (10.1016/j.cell.2012.11.025)
Abstract HLA-DR molecules bind microbial peptides in an endosomal compartment and present them on the cell surface for CD4 T cell surveillance. HLA-DM plays a critical role in the endosomal peptide selection process. The structure of the HLA-DM-HLA-DR complex shows major rearrangements of the HLA-DR peptide-binding groove. Flipping of a tryptophan away from the HLA-DR1 P1 pocket enables major conformational changes that position hydrophobic HLA-DR residues into the P1 pocket. These conformational changes accelerate peptide dissociation and stabilize the empty HLA-DR peptide-binding groove. Initially, incoming peptides have access to only part of the HLA-DR groove and need to compete with HLA-DR residues for access to the P2 site and the hydrophobic P1 pocket. This energetic barrier creates a rapid and stringent selection process for the highest-affinity binders. Insertion of peptide residues into the P2 and P1 sites reverses the conformational changes, terminating selection through DM dissociation.
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