Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit
| العنوان: | Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit |
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| المؤلفون: | Xiaolei Ma, Gladys T. Muiru, Vincent H. J. Leonard, Yongjin Xu, Dirksen E. Bussiere, Weidong Zhong, Charles Wartchow, David C. Tully, Warne Robert L, Steven Shia, Kyoko Uehara, Alexey Rivkin, Isabel Zaror, Lili Xie, Dianna M. Baldwin |
| المصدر: | Scientific Reports, Vol 7, Iss 1, Pp 1-8 (2017) Scientific Reports |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Models, Molecular, 0301 basic medicine, Science, viruses, Protein subunit, Molecular Conformation, Biology, medicine.disease_cause, Antiviral Agents, Article, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Transcription (biology), RNA polymerase, Heterotrimeric G protein, Influenza A virus, medicine, Viral structural protein, Humans, Binding site, Polymerase, Binding Sites, Multidisciplinary, Molecular Structure, virus diseases, biochemical phenomena, metabolism, and nutrition, RNA-Dependent RNA Polymerase, Molecular biology, Cell biology, Protein Subunits, 030104 developmental biology, chemistry, biology.protein, Medicine, Protein Binding |
| الوصف: | Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11–13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787. |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::676683a0bba30d0c344634542d5a6e86 https://doi.org/10.1038/s41598-017-09538-x |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....676683a0bba30d0c344634542d5a6e86 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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