Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860,ACS Infectious Diseases

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Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-06-28 00:00:00 , DOI: 10.1021/acsinfecdis.7b00053
Minetaro Arita ₁ , Georgi Dobrikov ₂ , Gerhard Pürstinger ₃ , Angel S. Galabov ₄

Affiliation

MDL-860 is a broad-spectrum antipicornavirus compound discovered in 1982 and one of the few promising candidates effective in in vivo virus infection. Despite the effectiveness, the target and the mechanism of action of MDL-860 remain unknown. Here, we have characterized antipoliovirus activity of MDL-860 and identified host phosphatidylinositol-4 kinase III beta (PI4KB) as the target. MDL-860 treatment caused covalent modification and irreversible inactivation of PI4KB. A cysteine residue at amino acid 646 of PI4KB, which locates at the bottom of a surface pocket apart from the active site, was identified as the target site of MDL-860. This work reveals the mechanism of action of this class of PI4KB inhibitors and offers insights into novel allosteric regulation of PI4KB activity.

中文翻译：

抗小核糖核酸病毒化合物MDL-860对磷脂酰肌醇4-激酶III Beta的变构调节。

MDL-860是一种广谱抗幽门螺杆菌化合物，于1982年发现，是在体内病毒感染中有效的少数有前途的候选药物之一。尽管有效，但MDL-860的靶标和作用机制仍然未知。在这里，我们表征了MDL-860的抗脊髓灰质炎病毒活性，并将宿主磷脂酰肌醇4激酶III beta（PI4KB）确定为目标。MDL-860处理引起PI4KB的共价修饰和不可逆失活。位于PI4KB氨基酸646处的半胱氨酸残基位于与活动位点分开的表面袋的底部，被鉴定为MDL-860的目标位点。这项工作揭示了这类PI4KB抑制剂的作用机理，并为PI4KB活性的新型变构调节提供了见识。

更新日期：2017-06-28

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