4M9F

Dengue virus NS2B-NS3 protease A125C variant at pH 8.5

4M9F の概要

• エントリーDOI: 10.2210/pdb4m9f/pdb
• 関連するPDBエントリー: 2fom 3U1I 3U1J 4M9I 4M9K 4M9M 4M9T
• 分子名称: NS2B-NS3 protease (2 entities in total)
• 機能のキーワード: serine protease, allosteric inhibition, dengue virus protease, trypsin-like protease, conformational flexibility, viral protein
• 由来する生物種: Dengue virus 2; 詳細
• 細胞内の位置: Virion membrane ; Multi-pass membrane protein : Q91H74
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26360.48

構造登録者

Yildiz, M.,Ghosh, S.,Bell, J.A.,Sherman, W.,Hardy, J.A. (登録日: 2013-08-14, 公開日: 2013-11-27, 最終更新日: 2023-09-20)

主引用文献

Yildiz, M.,Ghosh, S.,Bell, J.A.,Sherman, W.,Hardy, J.A.
Allosteric Inhibition of the NS2B-NS3 Protease from Dengue Virus.
Acs Chem.Biol., 8:2744-2752, 2013

PubMed Abstract: Dengue virus is the flavivirus that causes dengue fever, dengue hemorrhagic disease, and dengue shock syndrome, which are currently increasing in incidence worldwide. Dengue virus protease (NS2B-NS3pro) is essential for dengue virus infection and is thus a target of therapeutic interest. To date, attention has focused on developing active-site inhibitors of NS2B-NS3pro. The flat and charged nature of the NS2B-NS3pro active site may contribute to difficulties in developing inhibitors and suggests that a strategy of identifying allosteric sites may be useful. We report an approach that allowed us to scan the NS2B-NS3pro surface by cysteine mutagenesis and use cysteine reactive probes to identify regions of the protein that are susceptible to allosteric inhibition. This method identified a new allosteric site utilizing a circumscribed panel of just eight cysteine variants and only five cysteine reactive probes. The allosterically sensitive site is centered at Ala125, between the 120s loop and the 150s loop. The crystal structures of WT and modified NS2B-NS3pro demonstrate that the 120s loop is flexible. Our work suggests that binding at this site prevents a conformational rearrangement of the NS2B region of the protein, which is required for activation. Preventing this movement locks the protein into the open, inactive conformation, suggesting that this site may be useful in the future development of therapeutic allosteric inhibitors.

PubMed: 24164286
DOI: 10.1021/cb400612h

実験手法

X-RAY DIFFRACTION (2.7 Å)