Noble metals strip peptides from class II MHC proteins.
Class II major histocompatibility complex (MHC) proteins are essential for normal immune system function but also drive many autoimmune responses. They bind peptide antigens in endosomes and present them on the cell surface for recognition by CD4(+) T cells. A small molecule could potentially block an autoimmune response by disrupting MHC-peptide interactions, but this has proven difficult because peptides bind tightly and dissociate slowly from MHC proteins. Using a high-throughput screening assay we discovered a class of noble metal complexes that strip peptides from human class II MHC proteins by an allosteric mechanism. Biochemical experiments indicate the metal-bound MHC protein adopts a 'peptide-empty' conformation that resembles the transition state of peptide loading. Furthermore, these metal inhibitors block the ability of antigen-presenting cells to activate T cells. This previously unknown allosteric mechanism may help resolve how gold(I) drugs affect the progress of rheumatoid arthritis and may provide a basis for developing a new class of anti-autoimmune drugs.
De Wall
Stephen L
SL
Institute of Chemistry and Cell Biology, Harvard Medical School, 200 Longwood Ave., Boston, Massachusetts 02115, USA.
Painter
Corrie
C
Stone
Jennifer D
JD
Bandaranayake
Rajintha
R
Wiley
Don C
DC
Mitchison
Timothy J
TJ
Stern
Lawrence J
LJ
DeDecker
Brian S
BS
D000495:Allosteric Site; D000818:Animals; D017951:Antigen Presentation; D001327:Autoimmune Diseases / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002850:Chromatography, Gel; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster; D004797:Enzyme-Linked Immunosorbent Assay; D006052:Gold Sodium Thiomalate / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008285:Major Histocompatibility Complex; D015233:Models, Statistical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D012973:Sodium Hypochlorite / Q000494:pharmacology; D013997:Time Factors
D000949:Histocompatibility Antigens Class II; D010455:Peptides; D006052:Gold Sodium Thiomalate; D012973:Sodium Hypochlorite; D002945:Cisplatin