6E5B

Human Immunoproteasome 20S particle in complex with compound 1

6E5B の概要

• エントリーDOI: 10.2210/pdb6e5b/pdb
• 分子名称: Proteasome subunit alpha type-2, Proteasome subunit beta type-2, Proteasome subunit beta type-8, ... (18 entities in total)
• 機能のキーワード: multicatalytic proteinase, 20s proteasome, protease, proteros, proteros biostructures gmbh, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 761477.64

構造登録者

Steinbacher, S.,Augustin, M.,Blaesse, M.,Harris, S.F. (登録日: 2018-07-19, 公開日: 2019-09-11, 最終更新日: 2024-10-23)

主引用文献

Ladi, E.,Everett, C.,Stivala, C.E.,Daniels, B.E.,Durk, M.R.,Harris, S.F.,Huestis, M.P.,Purkey, H.E.,Staben, S.T.,Augustin, M.,Blaesse, M.,Steinbacher, S.,Eidenschenk, C.,Pappu, R.,Siu, M.
Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability.
J.Med.Chem., 62:7032-7041, 2019

PubMed Abstract: The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism of this clinical benefit is from the depletion of pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, bortezomib is cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative is to selectively inhibit the immune cell-specific immunoproteasome to deplete pathogenic immune cells and spare nonhematopoietic cells. Here, we disclose the development of highly subunit-selective immunoproteasome inhibitors using insights obtained from the first bona fide human immunoproteasome cocrystal structures. Evaluation of these inhibitors revealed that immunoproteasome-specific inhibition does not lead to immune cell death as anticipated and that targeting viability requires inhibition of both immuno- and constitutive proteasomes. CRISPR/Cas9-mediated knockout experiments confirmed upregulation of the constitutive proteasome upon disruption of the immunoproteasome, protecting cells from death. Thus, immunoproteasome inhibition alone is not a suitable approach to deplete immune cells.

PubMed: 31283222
DOI: 10.1021/acs.jmedchem.9b00509

実験手法

X-RAY DIFFRACTION (2.77 Å)