5J40

The X-ray structure of JCV Helicase

5J40 の概要

• エントリーDOI: 10.2210/pdb5j40/pdb
• 関連するPDBエントリー: 5J47 5J4V 5J4Y
• 分子名称: Large T antigen, ZINC ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: helicase, hexamer, zn, atp, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: JC polyomavirus (JCPyV)
• 細胞内の位置: Host nucleus : P03072
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42745.69

構造登録者

Ter Haar, E. (登録日: 2016-03-31, 公開日: 2016-07-20, 最終更新日: 2024-03-06)

主引用文献

Bonafoux, D.,Nanthakumar, S.,Bandarage, U.K.,Memmott, C.,Lowe, D.,Aronov, A.M.,Bhisetti, G.R.,Bonanno, K.C.,Coll, J.,Leeman, J.,Lepre, C.A.,Lu, F.,Perola, E.,Rijnbrand, R.,Taylor, W.P.,Wilson, D.,Zhou, Y.,Zwahlen, J.,Ter Haar, E.
Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.
J.Med.Chem., 59:7138-7151, 2016

PubMed Abstract: There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 μM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 μM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.

PubMed: 27385654
DOI: 10.1021/acs.jmedchem.6b00486

実験手法

X-RAY DIFFRACTION (2.17 Å)