Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01760-5
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Funding
- Alliance for Lupus Research [255848]
- Daedalus Fund for Innovation of Weill Cornell Medicine
- Milstein Program in Translational Medicine and Chemical Biology
- American Heart Association (AHA Award) [13FTF17000018]
- American Diabetes Association (ADA award) [1-17-IBS-206]
- National Institutes of Health [R01 AI70285, U24 GM116787, R21 AI101393, AI123794, T32 DK007527]
- William Randolph Hearst Foundation
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Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells. Toxicity should be minimized by reversible inhibition of the immunoproteasome beta 5i subunit while sparing the constitutive beta 5c subunit. Here we report beta 5i-selective inhibition by asparagine-ethylenediamine (AsnEDA)-based compounds and present the high-resolution cryo-EM structural analysis of the human immunoproteasome. Despite inhibiting noncompetitively, an AsnEDA inhibitor binds the active site. Hydrophobic interactions are accompanied by hydrogen bonding with beta 5i and beta 6 subunits. The inhibitors are far more cytotoxic for myeloma and lymphoma cell lines than for hepatocarcinoma or non-activated lymphocytes. They block human B-cell proliferation and promote apoptotic cell death selectively in antibody-secreting B cells, and to a lesser extent in activated human T cells. Reversible, beta 5i-selective inhibitors may be useful for treatment of diseases involving activated or neoplastic B cells or activated T cells.
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