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Structure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated lymphocytes.

TitleStructure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated lymphocytes.
Publication TypeJournal Article
Year of Publication2017
AuthorsSantos Rde Luna Al, Bai L, Singh PK, Murakami N, Fan H, Zhan W, Zhu Y, Jiang X, Zhang K, Assker JPierre, Nathan C, Li H, Azzi J, Lin G
JournalNat Commun
Volume8
Issue1
Pagination1692
Date Published2017 11 22
ISSN2041-1723
KeywordsAsparagine, B-Lymphocytes, Binding Sites, Cell Line, Tumor, Cryoelectron Microscopy, Humans, Lymphocyte Activation, Lymphocytes, Models, Molecular, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Subunits, Static Electricity, T-Lymphocytes
Abstract

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 β5i subunit while sparing the constitutive β5c subunit. Here we report β5i-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 β5i and β6 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, β5i-selective inhibitors may be useful for treatment of diseases involving activated or neoplastic B cells or activated T cells.

DOI10.1038/s41467-017-01760-5
Alternate JournalNat Commun
PubMed ID29167449
PubMed Central IDPMC5700161
Grant ListR01 AI070285 / AI / NIAID NIH HHS / United States
U24 GM116787 / GM / NIGMS NIH HHS / United States
R21 AI101393 / AI / NIAID NIH HHS / United States
R21 AI123794 / AI / NIAID NIH HHS / United States
T32 DK007527 / DK / NIDDK NIH HHS / United States

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