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

Ruda de Luna Almeida Santos, Lin Bai, Pradeep K. Singh, Naoka Murakami, Hao Fan, Wenhu Zhan, Yingrong Zhu, Xiuju Jiang, Kaiming Zhang, Jean Pierre Assker, Carl F. Nathan, Huilin Li (), Jamil Azzi () and Gang Lin ()
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Ruda de Luna Almeida Santos: Van Andel Research Institute
Lin Bai: Van Andel Research Institute
Pradeep K. Singh: Weill Cornell Medicine
Naoka Murakami: Renal Division, Brigham and Women’s Hospital, Harvard Medical School
Hao Fan: Weill Cornell Medicine
Wenhu Zhan: Weill Cornell Medicine
Yingrong Zhu: Weill Cornell Medicine
Xiuju Jiang: Weill Cornell Medicine
Kaiming Zhang: Baylor College of Medicine
Jean Pierre Assker: Renal Division, Brigham and Women’s Hospital, Harvard Medical School
Carl F. Nathan: Weill Cornell Medicine
Huilin Li: Van Andel Research Institute
Jamil Azzi: Renal Division, Brigham and Women’s Hospital, Harvard Medical School
Gang Lin: Weill Cornell Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01760-5

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