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Structure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated 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 ?5i subunit while sparing the constitutive ?5c subunit. Here we report ?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 ?5i and ?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, ?5i-selective inhibitors may be useful for treatment of diseases involving activated or neoplastic B cells or activated T cells.

SUBMITTER: Santos RLA

PROVIDER: S-EPMC5700161 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Santos Ruda de Luna Almeida RLA Bai Lin L Singh Pradeep K PK Murakami Naoka N Fan Hao H Zhan Wenhu W Zhu Yingrong Y Jiang Xiuju X Zhang Kaiming K Assker Jean Pierre JP Nathan Carl F CF Li Huilin H Azzi Jamil J Lin Gang G

Nature communications 20171122 1

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 inh ...[more]

PMID: 29167449

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Dataset Information

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

Publications

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

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