Identification of the HLA-DM/HLA-DR interface.
Human leukocyte antigen (HLA)-DM is a critical participant in antigen presentation that catalyzes the dissociation of the Class II-associated Invariant chain-derived Peptide (CLIP) from the major histocompatibility complex (MHC) Class II molecules. There is competition amongst peptides for access to an MHC Class II groove and it has been hypothesised that DM functions as a 'peptide editor' that catalyzes the replacement of one peptide for another within the groove. It is established that the DM catalyst interacts directly with the MHC Class II but the precise location of the interface is unknown. Here, we combine previously described mutational data with molecular docking and energy minimisation simulations to identify a putative interaction site of >4000A2 which agrees with known point mutational data for both the DR and DM molecule. The docked structure is validated by comparison with experimental data and previously determined properties of protein-protein interfaces. A possible dissociation mechanism is suggested by the presence of an acidic cluster near the N terminus of the bound peptide.
Davies
Matthew N
MN
Edward Jenner Institute, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Headington, Oxford OX3 9DU, UK.
Lamikanra
Abigail
A
Sansom
Clare E
CE
Flower
Darren R
DR
Moss
David S
DS
Travers
Paul J
PJ
D017951:Antigen Presentation; D001665:Binding Sites; D006681:HLA-D Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D017354:Point Mutation; D011485:Protein Binding; D013816:Thermodynamics
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens