Letter abstract


Nature Chemical Biology 2, 197 - 201 (2006)
Published online: 26 February 2006 | doi:10.1038/nchembio773

Noble metals strip peptides from class II MHC proteins

Stephen L De Wall1,2,6,8, Corrie Painter3, Jennifer D Stone4, Rajintha Bandaranayake3, Don C Wiley5,7, Timothy J Mitchison1,2, Lawrence J Stern3,4 & Brian S DeDecker1,8

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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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  1. Institute of Chemistry and Cell Biology, Harvard Medical School, 200 Longwood Ave., Boston, Massachusetts 02115, USA.
  2. Department of Systems Biology, Harvard Medical School, 200 Longwood Ave., Boston, Massachusetts 02115, USA.
  3. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  4. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  5. Howard Hughes Medical Institute and Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
  6. Present address: Dade Behring, Inc., P.O. Box 6101, Newark, Delaware 19714, USA.
  7. Deceased.
  8. These authors contributed equally to this work.

Correspondence to: Brian S DeDecker1,8 e-mail: bdedecker@partners.org



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