title: Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection.
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.
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Wouter
authors.initials: W
authors.lastname: Pos
authors.forename: Dhruv K
authors.initials: DK
authors.lastname: Sethi
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Call
authors.forename: Monika-Sarah E D
authors.initials: MS
authors.lastname: Schulze
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Anders
authors.forename: Jason
authors.initials: J
authors.lastname: Pyrdol
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D006681:HLA-D Antigens / Q000737:chemistry* / Q000378:metabolism*; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015798:HLA-DR1 Antigen