EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Substrate recognition and cleavage mechanism of the monkeypox virus core protease.
ジャーナル・号・ページ	Nature, Vol. 643, Issue 8070, Page 271-279, Year 2025
掲載日	2025年4月22日
著者	Yan Gao / Xiong Xie / Xiaoyu Zhang / Junyuan Cao / Weiqi Lan / Tian You / Dongxu Li / Xuxue Dong / Wenhao Dai / Yingchun Xiang / Shulei Hu / Weijuan Shang / Botao Wu / Yumin Zhang / Jin Xu / Xiaoce Liu / Haofeng Wang / Wanlong Hu / Mingjing Zhang / Yinkai Duan / Wen Cui / Hao Zhou / Shengjiang Mao / Handi Jia / Zhanqi Sun / Menghan Jia / Yue Yin / Henry C Nguyen / Kailin Yang / Bei Yang / Xiuna Yang / Xiaoyun Ji / Gengfu Xiao / Wei Wang / Leike Zhang / Zihe Rao / Hong Liu / Haitao Yang /
PubMed 要旨	Poxviruses cause severe diseases, including smallpox and mpox, that pose major threats to human health. The poxvirus core protease (Core) is essential for viral maturation and is highly conserved in ...Poxviruses cause severe diseases, including smallpox and mpox, that pose major threats to human health. The poxvirus core protease (Core) is essential for viral maturation and is highly conserved in poxviruses, making it an attractive antiviral target. However, the structure of Core remains unknown, hampering antiviral development. Here we determined the apo structure of monkeypox virus (MPXV) Core and the structure of Core in a complex with the inhibitor aloxistatin, a drug candidate for muscular dystrophy. These structures show that Core forms a homodimer that features a unique 'dancing couple' fold. The catalytic intermediate state of Core was characterized by an aldehyde derivative from a natural substrate (I-G18). This derivative binds covalently to the catalytic Cys328, shifting the active site of the viral protease from a closed conformation in the apo form to a favourable open conformation upon substrate binding. On the basis of the Core-I-G18 complex, we designed a series of peptidomimetic inhibitors with a nitrile warhead, which could covalently anchor with the catalytic Cys328. These compounds inhibit Core with half-maximal inhibitory concentrations of 44.9-100.3 nM, and exhibit potent and broad anti-poxvirus activity. Our studies provide a basis for designing wide-spectrum inhibitors against poxvirus infections.
リンク	Nature / PubMed:40262633
手法	EM (単粒子) / X線回折
解像度	1.895 - 3.03 Å
構造データ	61292 9jal EMDB-61292, PDB-9jal: Cryo-EM structure of MPXV core protease in complex with compound A1 手法: EM (単粒子) / 解像度: 3.03 Å 61293 9jam EMDB-61293, PDB-9jam: Cryo-EM structure of MPXV core protease in complex with compound A3 手法: EM (単粒子) / 解像度: 2.98 Å 61294 9jan EMDB-61294, PDB-9jan: Cryo-EM structure of MPXV protease in complex with compound A4 手法: EM (単粒子) / 解像度: 2.93 Å 61300 9jaq EMDB-61300, PDB-9jaq: Cryo-EM structure of MPXV core protease in the apo-form 手法: EM (単粒子) / 解像度: 2.99 Å 62516 9kqv EMDB-62516, PDB-9kqv: Cryo-EM structure of MPXV core protease in complex with aloxistatin(E64d) 手法: EM (単粒子) / 解像度: 2.93 Å 62520 9kr6 EMDB-62520, PDB-9kr6: Cryo-EM structure of MPXV core protease in complex with the substrate derivative I-G18 手法: EM (単粒子) / 解像度: 2.8 Å PDB-9ku2: Structure of taterapox core protease central domain 手法: X-RAY DIFFRACTION / 解像度: 1.895 Å PDB-9ku9: Structure of mpox core protease mutant 手法: X-RAY DIFFRACTION / 解像度: 2.199 Å
化合物	ChemComp-E6D: ethyl (3S)-3-hydroxy-4-({(2S)-4-methyl-1-[(3-methylbutyl)amino]-1-oxopentan-2-yl}amino)-4-oxobutanoate ChemComp-HOH: WATER
由来	monkeypox virus (サル痘ウイルス) synthetic construct (人工物) taterapox virus (ウイルス)
キーワード	VIRAL PROTEIN / Orthopoxviruses / mpox / Protease / Viral replication / Drug discovery / inhibitor / Monkeypox / E64D / orthopoxvirus