6CRN

Structure of the USP15 deubiquitinase domain in complex with a high-affinity first-generation Ubv

6CRN の概要

• エントリーDOI: 10.2210/pdb6crn/pdb
• 関連するPDBエントリー: 6CPM 6CSI
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 15, Ubiquitin variant 15.2, ZINC ION, ... (4 entities in total)
• 機能のキーワード: deubiuqitination, ubv, high-affinity, inhibition, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 200396.50

構造登録者

Singer, A.U.,Teyra, J.,Boehmelt, G.,Lenter, M.,Sicheri, F.,Sidhu, S.S. (登録日: 2018-03-19, 公開日: 2019-01-23, 最終更新日: 2024-10-16)

主引用文献

Teyra, J.,Singer, A.U.,Schmitges, F.W.,Jaynes, P.,Kit Leng Lui, S.,Polyak, M.J.,Fodil, N.,Krieger, J.R.,Tong, J.,Schwerdtfeger, C.,Brasher, B.B.,Ceccarelli, D.F.J.,Moffat, J.,Sicheri, F.,Moran, M.F.,Gros, P.,Eichhorn, P.J.A.,Lenter, M.,Boehmelt, G.,Sidhu, S.S.
Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15.
Structure, 27:590-, 2019

PubMed Abstract: The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designed a linear dimer (diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced specificity and more potent inhibition of catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor β pathway. Structural analyses revealed that three distinct UbVs bound to the catalytic domain and locked the active site in a closed, inactive conformation, and one UbV formed an unusual strand-swapped dimer and bound two DUSP domains simultaneously. These inhibitors will enable the study of USP15 function in oncology, neurology, immunology, and inflammation.

PubMed: 30713027
DOI: 10.1016/j.str.2019.01.002

実験手法

X-RAY DIFFRACTION (2.5 Å)