期刊
CELL
卷 151, 期 7, 页码 1557-1568出版社
CELL PRESS
DOI: 10.1016/j.cell.2012.11.025
关键词
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资金
- National Institutes of Health [RO1 NS044914, PO1 AI045757]
- National Multiple Sclerosis Society
- American Diabetes Association
- Ruth L. Kirschstein National Research Service Award
- National Center for Research Resources [5P41RR015301-10]
- National Institute of General Medical Sciences from the National Institutes of Health [8P41 GM103403-10]
- U.S. DOE [DE-AC02-06CH11357]
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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