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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 cells1. 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 mechanism2. 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.

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Figure 1: Square-planar noble metal complexes release peptide from DR1.
Figure 2: Metal-mediated peptide dissociation kinetics and loss of peptide-binding activity by cisplatin-modified DR1 indicate that the metal complexes are noncompetitive inhibitors.
Figure 3: Metal-modified DR1 adopts a stable, peptide-empty conformational state that is recognized by DM.
Figure 4: The in vitro inhibitory activity of these metal complexes correlates with their ability to block T cell activation.


  1. Watts, C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu. Rev. Immunol. 15, 821–850 (1997).

    Article  CAS  Google Scholar 

  2. DeDecker, B.S. Allosteric drugs: thinking outside the active-site box. Chem. Biol. 7, R103–R107 (2000).

    Article  CAS  Google Scholar 

  3. Morris, P. et al. An essential role for HLA-DM in antigen presentation by class II major histocompatibility molecules. Nature 368, 551–554 (1994).

    Article  CAS  Google Scholar 

  4. Weber, D.A., Evavold, B.D. & Jensen, P.E. Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM. Science 274, 618–620 (1996).

    Article  CAS  Google Scholar 

  5. Kato, M. et al. Inhibition of Thermus thermophilus HB8 thioredoxin activity by platinum(II). J. Chem. Soc., Dalton Trans. 6, 1023–1026 (2005).

    Article  Google Scholar 

  6. Isab, A.A. & Sadler, P.J. Reactions of gold(III) ions with ribonuclease A and methionine derivatives in aqueous solution. Biochim. Biophys. Acta 492, 322–330 (1977).

    Article  CAS  Google Scholar 

  7. Fakih, S. et al. Novel adducts of the anticancer drug oxaliplatin with glutathione and redox reactions with glutathione disulfide. Eur. J. Inorg. Chem. 6, 1206–1214 (2003).

    Article  Google Scholar 

  8. Richens, D.T. Ligand substitution reactions at inorganic centers. Chem. Rev. 105, 1961–2002 (2005).

    Article  CAS  Google Scholar 

  9. Lazarski, C.A. et al. The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance. Immunity 23, 29–40 (2005).

    Article  CAS  Google Scholar 

  10. Sherman, M.A., Weber, D.A. & Jensen, P.E. DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity 3, 197–205 (1995).

    Article  CAS  Google Scholar 

  11. Carven, G.J. et al. Monoclonal antibodies specific for the empty conformation of HLA-DR1 reveal aspects of the conformational change associated with peptide binding. J. Biol. Chem. 279, 16561–16570 (2004).

    Article  CAS  Google Scholar 

  12. Stratikos, E., Mosyak, L., Zaller, D.M. & Wiley, D.C. Identification of the lateral interaction surfaces of human histocompatibility leukocyte antigen (HLA)-DM with HLA-DR1 by formation of tethered complexes that present enhanced HLA-DM catalysis. J. Exp. Med. 196, 173–183 (2002).

    Article  CAS  Google Scholar 

  13. Kean, W.F., Hart, L. & Buchanan, W.W. Auranofin. Br. J. Rheumatol. 36, 560–572 (1997).

    Article  CAS  Google Scholar 

  14. Griem, P., Takahashi, K., Kalbacher, H. & Gleichmann, E. The antirheumatic drug disodium aurothiomalate inhibits CD4+ T cell recognition of peptides containing two or more cysteine residues. J. Immunol. 155, 1575–1587 (1995).

    CAS  PubMed  Google Scholar 

  15. Takahashi, K., Kropshofer, H., Vogt, A.B., Gleichmann, E. & Griem, P. Drug-induced inhibition of insulin recognition by T-cells: the antirheumatic drug aurothiomalate inhibits MHC binding of insulin peptide. Mol. Immunol. 35, 1081–1087 (1998).

    Article  CAS  Google Scholar 

  16. Goebel, C., Kubicka-Muranyi, M., Tonn, T., Gonzalez, J. & Gleichmann, E. Phagocytes render chemicals immunogenic: oxidation of gold(I) to the T cell-sensitizing gold(III) metabolite generated by mononuclear phagocytes. Arch. Toxicol. 69, 450–459 (1995).

    Article  CAS  Google Scholar 

  17. Shaw, C.F. et al. Redox chemistry and [Au(CN)2] in the formation of gold metabolites. Metal Based Drugs 1, 351–362 (1994).

    Article  CAS  Google Scholar 

  18. Griem, P., Panthel, K., Kalbacher, H. & Gleichmann, E. Alteration of a model antigen by Au(III) leads to T cell sensitization to cryptic peptides. Eur. J. Immunol. 26, 279–287 (1996).

    Article  CAS  Google Scholar 

  19. Romagnoli, P., Spinas, G.A. & Sinigaglia, F. Gold-specific T cells in rheumatoid arthritis patients treated with gold. J. Clin. Invest. 89, 254–258 (1992).

    Article  CAS  Google Scholar 

  20. Verwilghen, J., Kingsley, G.H., Gambling, L. & Panayi, G.S. Activation of gold-reactive T lymphocytes in rheumatoid arthritis patients treated with gold. Arthritis Rheum. 35, 1413–1418 (1992).

    Article  CAS  Google Scholar 

  21. Babior, B.M., Kipnes, R.S. & Curnutte, J.T. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J. Clin. Invest. 52, 741–744 (1973).

    Article  CAS  Google Scholar 

  22. Hashimoto, K., Whitehurst, C.E., Matsubara, T., Hirohata, K. & Lipsky, P.E. Immunomodulatory effects of therapeutic gold compounds. Gold sodium thiomalate inhibits the activity of T cell protein kinase C. J. Clin. Invest. 89, 1839–1848 (1992).

    Article  CAS  Google Scholar 

  23. Koch, R. Uber Bacteriologische Forschung: Tenth International Medical Congress. Dtsch. Med. Wochenstr. 16, 756–757 (1890).

    Google Scholar 

  24. Forestier, J. Rheumatoid arthritis and its treatment with gold salts - results of six years experience. J. Lab. Clin. Med. 20, 827 (1935).

    Google Scholar 

  25. Bowen, J.R., Gale, G.R., Gardner, W.A., Jr. & Bonner, W.M., Jr. Cis-dichlorodiammineplatinum (II): suppression of adjuvant-induced arthritis in rats. Agents Actions 4, 108–112 (1974).

    Article  CAS  Google Scholar 

  26. Sanchez-Burson, J., Aparicio, L.A., Mendez, M. & Galdo, F. cis-platinum, a treatment for refractory rheumatoid arthritis? Br. J. Rheumatol. 28, 358 (1989).

    Article  CAS  Google Scholar 

  27. Rau, R. Have traditional DMARDs had their day? Effectiveness of parenteral gold compared to biologic agents. Clin. Rheumatol. 24, 189–202 (2005).

    Article  Google Scholar 

  28. Louie, A.Y. & Meade, T.J. Metal complexes as enzyme inhibitors. Chem. Rev. 99, 2711–2734 (1999).

    Article  CAS  Google Scholar 

  29. Boen, E., Crownover, A.R., McIlhaney, M., Korman, A.J. & Bill, J. Identification of T cell ligands in a library of peptides covalently attached to HLA-DR4. J. Immunol. 165, 2040–2047 (2000).

    Article  CAS  Google Scholar 

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We thank R. Ward for fostering this work from its inception; S. Harrison for support and discussions; C. Shamu and the Institute of Chemistry and Cell Biology–Longwood screening facility for screening resources and expertise; A. Haykov for technical assistance; Q. Liu for a critical chemical library acquisition; T. Rapoport and G. Voeltz for helpful comments and J. Bill for providing the T cell hybridoma. This work was supported in part by a Juvenile Diabetes Research Foundation International Research Grant (T.J.M.) and the Howard Hughes Medical Institute (HHMI) (D.C.W.). Additional support for this work was provided by an American Diabetes Association Mentor-based Postdoctoral Fellowship (D.C.W.) and the National Institute of Allergy and Infectious Diseases (grant numbers 5 T32 AI07245-20 and ROI-AI 38996 (L.J.S.)). D.C.W. was an investigator in the HHMI.

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Correspondence to Brian S DeDecker.

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Supplementary information

Supplementary Fig. 1

Activity of metal complexes is independent of buffer and pH. (PDF 75 kb)

Supplementary Fig. 2

DMSO concentration has no effect on the inhibitory activity of the metals (PDF 124 kb)

Supplementary Fig. 3

Stability of metal-DR1 and peptide-DR1 complexes by SDS-PAGE (PDF 130 kb)

Supplementary Methods (PDF 150 kb)

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De Wall, S., Painter, C., Stone, J. et al. Noble metals strip peptides from class II MHC proteins. Nat Chem Biol 2, 197–201 (2006).

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