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Noble metals strip peptides from class II MHC proteins

Nature Chemical Biology volume 2, pages 197–201 (2006)Cite this article

Abstract

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.

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Acknowledgements

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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Author notes

  1. Stephen L De Wall

    Present address: Dade Behring, Inc., P.O. Box 6101, Newark, Delaware, 19714, USA

  2. Don C Wiley: Deceased.

  3. Stephen L De Wall and Brian S DeDecker: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Chemistry and Cell Biology, Harvard Medical School, 200 Longwood Ave., Boston, 02115, Massachusetts, USA

    Stephen L De Wall, Timothy J Mitchison & Brian S DeDecker

  2. Department of Systems Biology, Harvard Medical School, 200 Longwood Ave., Boston, 02115, Massachusetts, USA

    Stephen L De Wall & Timothy J Mitchison

  3. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, 01655, Massachusetts, USA

    Corrie Painter, Rajintha Bandaranayake & Lawrence J Stern

  4. Department of Pathology, University of Massachusetts Medical School, Worcester, 01655, Massachusetts, USA

    Jennifer D Stone & Lawrence J Stern

  5. Howard Hughes Medical Institute and Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, 02138, Massachusetts, USA

    Don C Wiley

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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). https://doi.org/10.1038/nchembio773

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