Native Mass Spectrometry Reveals Binding Interactions of SARS-CoV-2 PLpro with Inhibitors and Cellular Targets

被引:0
|
作者
James, Virginia K. [1 ]
Godula, Rianna N. [2 ]
Perez, Jessica M. [2 ]
Beckham, Josh T. [3 ]
Butalewicz, Jamie P. [1 ]
Sipe, Sarah N. [1 ]
Huibregtse, Jon M. [2 ]
Brodbelt, Jennifer S. [1 ]
机构
[1] Univ Texas Austin, Dept Chem, Austin, TX 78712 USA
[2] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA
[3] Univ Texas Austin, Freshman Res Initiat, Austin, TX 78712 USA
来源
ACS INFECTIOUS DISEASES | 2024年 / 10卷 / 10期
基金
美国国家卫生研究院;
关键词
ultraviolet photodissociation; mass spectrometry; SARS-CoV protease; PLpro; inhibitor; protein-protein interactions; CROSS-LINKING; DISTANCE RESTRAINTS; PAPAIN-LIKE; PROTEIN; PR-619;
D O I
10.1021/acsinfecdis.4c00444
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Here we used native mass spectrometry (native MS) to probe a SARS-CoV protease, PLpro, which plays critical roles in coronavirus disease by affecting viral protein production and antagonizing host antiviral responses. Ultraviolet photodissociation (UVPD) and variable temperature electrospray ionization (vT ESI) were used to localize binding sites of PLpro inhibitors and revealed the stabilizing effects of inhibitors on protein tertiary structure. We compared PLpro from SARS-CoV-1 and SARS-CoV-2 in terms of inhibitor and ISG15 interactions to discern possible differences in protease function. A PLpro mutant lacking a single cysteine was used to localize inhibitor binding, and thermodynamic measurements revealed that inhibitor PR-619 stabilized the folded PLpro structure. These results will inform further development of PLpro as a therapeutic target against SARS-CoV-2 and other emerging coronaviruses.
引用
收藏
页码:3597 / 3606
页数:10
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