5F6Y

Crystal structure of Ubc9 (K48/K49A/E54A) complexed with Fragment 2 (mercaptobenzoxazole)

5F6Y の概要

• エントリーDOI: 10.2210/pdb5f6y/pdb
• 関連するPDBエントリー: 5F6D 5F6E 5F6U 5F6V 5F6W 5F6X
• 分子名称: SUMO-conjugating enzyme UBC9, 5-chloranyl-3~{H}-1,3-benzoxazole-2-thione (3 entities in total)
• 機能のキーワード: ubc9, fragment drug design, sumoylation, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: P63279
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17911.01

構造登録者

Lountos, G.T.,Hewitt, W.M.,Zlotkowski, K.,Dahlhauser, S.,Saunders, L.B.,Needle, D.,Tropea, J.E.,Zhan, C.,Wei, G.,Ma, B.,Nussinov, R.,Schneekloth, J.S.Jr.,Waugh, D.S. (登録日: 2015-12-07, 公開日: 2016-04-27, 最終更新日: 2023-09-27)

主引用文献

Hewitt, W.M.,Lountos, G.T.,Zlotkowski, K.,Dahlhauser, S.D.,Saunders, L.B.,Needle, D.,Tropea, J.E.,Zhan, C.,Wei, G.,Ma, B.,Nussinov, R.,Waugh, D.S.,Schneekloth, J.S.
Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.
Angew.Chem.Int.Ed.Engl., 55:5703-5707, 2016

PubMed Abstract: Conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important disease-associated posttranslational modification, although few inhibitors of this process are known. Herein, we report the discovery of an allosteric small-molecule binding site on Ubc9, the sole SUMO E2 enzyme. An X-ray crystallographic screen was used to identify two distinct small-molecule fragments that bind to Ubc9 at a site distal to its catalytic cysteine. These fragments and related compounds inhibit SUMO conjugation in biochemical assays with potencies of 1.9-5.8 mm. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition.

PubMed: 27038327
DOI: 10.1002/anie.201511351

実験手法

X-RAY DIFFRACTION (1.14 Å)