8P14

USP28 USP domain in complex with Vismodegib

8P14 の概要

• エントリーDOI: 10.2210/pdb8p14/pdb
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 28, 2-chloranyl-~{N}-(4-chloranyl-3-pyridin-2-yl-phenyl)-4-methylsulfonyl-benzamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: ubiquitin, inhibitor, deubiquitylase, oncoprotein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44589.12

構造登録者

Sauer, F.,Karal Nair, R.,Kisker, C. (登録日: 2023-05-11, 公開日: 2024-05-22, 最終更新日: 2024-12-04)

主引用文献

Patzke, J.V.,Sauer, F.,Nair, R.K.,Endres, E.,Proschak, E.,Hernandez-Olmos, V.,Sotriffer, C.,Kisker, C.
Structural basis for the bi-specificity of USP25 and USP28 inhibitors.
Embo Rep., 25:2950-2973, 2024

PubMed Abstract: The development of cancer therapeutics is often hindered by the fact that specific oncogenes cannot be directly pharmaceutically addressed. Targeting deubiquitylases that stabilize these oncogenes provides a promising alternative. USP28 and USP25 have been identified as such target deubiquitylases, and several small-molecule inhibitors indiscriminately inhibiting both enzymes have been developed. To obtain insights into their mode of inhibition, we structurally and functionally characterized USP28 in the presence of the three different inhibitors AZ1, Vismodegib and FT206. The compounds bind into a common pocket acting as a molecular sink. Our analysis provides an explanation why the two enzymes are inhibited with similar potency while other deubiquitylases are not affected. Furthermore, a key glutamate residue at position 366/373 in USP28/USP25 plays a central structural role for pocket stability and thereby for inhibition and activity. Obstructing the inhibitor-binding pocket by mutation of this glutamate may provide a tool to accelerate future drug development efforts for selective inhibitors of either USP28 or USP25 targeting distinct binding pockets.

PubMed: 38816515
DOI: 10.1038/s44319-024-00167-w

実験手法

X-RAY DIFFRACTION (2.57 Å)