6GH9

USP15 catalytic domain in complex with small molecule

6GH9 の概要

• エントリーDOI: 10.2210/pdb6gh9/pdb
• 関連するPDBエントリー: 6GHA
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 15, ZINC ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: protease, ubiquitin, ubiquitin specific protease, inhibitor, mitoxantrone, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84082.50

構造登録者

Ward, S.J.,Gratton, H.E.,Caulton, S.G.,Emsley, J.,Dreveny, I. (登録日: 2018-05-06, 公開日: 2018-09-26, 最終更新日: 2024-01-17)

主引用文献

Ward, S.J.,Gratton, H.E.,Indrayudha, P.,Michavila, C.,Mukhopadhyay, R.,Maurer, S.K.,Caulton, S.G.,Emsley, J.,Dreveny, I.
The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel.
J. Biol. Chem., 293:17362-17374, 2018

PubMed Abstract: Ubiquitin-specific protease 15 (USP15) regulates important cellular processes, including transforming growth factor β (TGF-β) signaling, mitophagy, mRNA processing, and innate immune responses; however, structural information on USP15's catalytic domain is currently unavailable. Here, we determined crystal structures of the USP15 catalytic core domain, revealing a canonical USP fold, including a finger, palm, and thumb region. Unlike for the structure of paralog USP4, the catalytic triad is in an inactive configuration with the catalytic cysteine ∼10 Å apart from the catalytic histidine. This conformation is atypical, and a similar misaligned catalytic triad has so far been observed only for USP7, although USP15 and USP7 are differently regulated. Moreover, we found that the active-site loops are flexible, resulting in a largely open ubiquitin tail-binding channel. Comparison of the USP15 and USP4 structures points to a possible activation mechanism. Sequence differences between these two USPs mainly map to the S1' region likely to confer specificity, whereas the S1 ubiquitin-binding pocket is highly conserved. Isothermal titration calorimetry monoubiquitin- and linear diubiquitin-binding experiments showed significant differences in their thermodynamic profiles, with USP15 displaying a lower affinity for monoubiquitin than USP4. Moreover, we report that USP15 is weakly inhibited by the antineoplastic agent mitoxantrone A USP15-mitoxantrone complex structure disclosed that the anthracenedione interacts with the S1' binding site. Our results reveal first insights into USP15's catalytic domain structure, conformational changes, differences between paralogs, and small-molecule interactions and establish a framework for cellular probe and inhibitor development.

PubMed: 30228188
DOI: 10.1074/jbc.RA118.003857

実験手法

X-RAY DIFFRACTION (2.09 Å)