9FT0

Yeast 20S proteasome in complex with epoxyketone inhibitor 16

これはPDB形式変換不可エントリーです。

9FT0 の概要

• エントリーDOI: 10.2210/pdb9ft0/pdb
• 関連するPDBエントリー: 5CZ4
• 分子名称: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (20 entities in total)
• 機能のキーワード: proteasome, inhibitor, structure-based drug development, binding analysis, hydrolase
• 由来する生物種: Saccharomyces cerevisiae (brewer's yeast); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 734795.73

構造登録者

Maurits, E.,Huber, E.M.,Dekker, P.M.,Wang, X.,Heinemeyer, W.,Florea, B.I.,Groll, M.,Overkleeft, H.S. (登録日: 2024-06-23, 公開日: 2024-07-10, 最終更新日: 2026-01-28)

主引用文献

Dekker, P.M.,Huber, E.M.,Maurits, E.,Wang, X.,Heinemeyer, W.,Florea, B.I.,Groll, M.,Overkleeft, H.S.
Structure-Based Design of Pan-Selective Peptide Epoxyketones for the Three Human Immunoproteasome Active Sites.
J.Med.Chem., 69:1247-1263, 2026

PubMed Abstract: The proteasome inhibitors bortezomib, carfilzomib, and ixazomib all act by inhibiting multiple active sites of both constitutive proteasomes and immunoproteasomes. These clinical anticancer drugs are effective, but also display side effects, and evidence is amassing that their toxicity arises from constitutive proteasome inhibition. In this work, we describe the structure-guided discovery of a new class of pan-immunoproteasome-selective inhibitors. We identified the peptide epoxyketone BocPip-Ser (), which targets all three human immunoproteasome active sites potently and with excellent selectivity over constitutive proteasome active sites (IC values for i-subunits ≤ 0.92 μM; IC ratio β1c/β1i: 13, β2c/β2i: 14, β5c/β5i: 18; Table 1 and Figure 3). We propose compound (BocPip-Ser), which is of a similar size and general properties as carfilzomib, as a lead compound for the development of improved drugs targeting hematological cancers, and possibly also autoimmune diseases, driven by immunoproteasome but not constitutive proteasome activities.

PubMed: 41504611
DOI: 10.1021/acs.jmedchem.5c02639

実験手法

X-RAY DIFFRACTION (2.75 Å)