8BZL

Human 20S Proteasome in complex with peptide activator peptide BLM42

8BZL の概要

• エントリーDOI: 10.2210/pdb8bzl/pdb
• 関連するPDBエントリー: 5LE5
• 分子名称: Proteasome subunit beta type-3, Proteasome subunit beta type-2, Proteasome subunit beta type-5, ... (21 entities in total)
• 機能のキーワード: activator peptide, 20s proteasome, protein degradation, threonine protease, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 34
• 化学式量合計: 777610.36

構造登録者

Henneberg, F.,Chari, A.,Jankowska, E.,Witkowska, J. (登録日: 2022-12-15, 公開日: 2023-12-27, 最終更新日: 2025-02-26)

主引用文献

Witkowska, J.,Gizynska, M.,Karpowicz, P.,Sowik, D.,Trepczyk, K.,Hennenberg, F.,Chari, A.,Gieldon, A.,Pierzynowska, K.,Gaffke, L.,Wegrzyn, G.,Jankowska, E.
Blm10-Based Compounds Add to the Knowledge of How Allosteric Modulators Influence Human 20S Proteasome.
Acs Chem.Biol., 2025

PubMed Abstract: Proteasomes catalyze protein degradation in cells and play an integral role in cellular homeostasis. Its activity decreases with age alongside the load of defective proteins, resulting from mutations or oxidative stress-induced damage. Such proteins are prone to aggregation and, if not efficiently degraded, can form toxic oligomers and amyloid plaques. Developing an effective way to activate the proteasome could prevent such pathologies. Designing activators is not easy because they do not bind in the active site, which is well-defined and highly conserved, but away from it. The structures of proteasome complexes with natural activators can help here, but these are large proteins, some even multimeric, whose activity is difficult to replace with a small-molecule compound. Nevertheless, the use of fragments of such proteins makes it possible to accumulate knowledge about the relevance of various structural elements for efficient and selective activation. Here, we presented peptidic activators of the 20S proteasome, which were designed based on both the -terminal sequence of the yeast proteasome activator, Blm10 protein, and the interactions predicted by molecular modeling. These Blm analogs were able to stimulate human 20S proteasome to more efficiently degrade both small fluorogenic substrates and proteins. The best activators also demonstrated their efficacy in cell lysates. X-ray crystallography indicated that an effective modulator can bind to several sites on the surface of the proteasome without causing permanent structural changes in its immediate vicinity but affecting the active sites.

PubMed: 39907714
DOI: 10.1021/acschembio.4c00341

実験手法

X-RAY DIFFRACTION (2.14 Å)