4gbx Citations

Crystal Structure of the HLA-DM-HLA-DR1 Complex Defines Mechanisms for Rapid Peptide Selection.


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.

Articles - 4gbx mentioned but not cited (1)

  1. HLA-Modeler: Automated Homology Modeling of Human Leukocyte Antigens. Amari S, Kataoka R, Ikegami T, Hirayama N. Int J Med Chem 2013 690513 (2013)

Reviews citing this publication (21)

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Articles citing this publication (24)

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  3. HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. Meza-Romero R, Benedek G, Yu X, Mooney JL, Dahan R, Duvshani N, Bucala R, Offner H, Reiter Y, Burrows GG, Vandenbark AA. J. Immunol. 192 4164-4173 (2014)
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  14. Disruption of hydrogen bonds between major histocompatibility complex class II and the peptide N-terminus is not sufficient to form a human leukocyte antigen-DM receptive state of major histocompatibility complex class II. Schulze MS, Anders AK, Sethi DK, Call MJ. PLoS ONE 8 e69228 (2013)
  15. MHC class II complexes sample intermediate states along the peptide exchange pathway. Wieczorek M, Sticht J, Stolzenberg S, Günther S, Wehmeyer C, El Habre Z, Álvaro-Benito M, Noé F, Freund C. Nat Commun 7 13224 (2016)
  16. pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic activity. Jiang W, Strohman MJ, Somasundaram S, Ayyangar S, Hou T, Wang N, Mellins ED. Sci Rep 5 17333 (2015)
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