https://doi.org/10.1016/j.apsb.2024.05.018
This new article publication from
Acta Pharmaceutica Sinica B, discusses how SARS-CoV-2 ORF10 hijacking ubiquitination machinery reveals potential unique drug targeting sites.
Viruses often manipulate ubiquitination pathways to facilitate their replication and pathogenesis. CUL2
ZYG11B known as the substrate receptor of cullin-2 RING E3 ligase, is bound by SARS-CoV-2 ORF10 to increase its E3 ligase activity, leading to degradation of IFT46, a protein component of the intraflagellar transport (IFT) complex B. This results in dysfunctional cilia, which explains certain symptoms that are specific to COVID-19.
However, the precise molecular mechanism of how ORF10 recognizes CUL2
ZYG11B remains unknown. The authors of this article determined the crystal structure of CUL2
ZYG11B complexed with the N-terminal extension (NTE) of SARS-CoV-2 ORF10 (2.9 Å). The structure reveals that the ORF10 N-terminal heptapeptide (NTH) mimics the Gly/N-degron to bind CUL2
ZYG11B. Mutagenesis studies identified key residues within ORF10 that are key players in its interaction with CUL2
ZYG11B both in ITC assay and
in vivo cells. In addition, enhancement of CUL2
ZYG11B activity for IFT46 degradation by which ORF10-mediated correlates with the binding affinity between ORF10 and CUL2
ZYG11B was proven. Finally, a Global Protein Stability system was used to show that the NTH of ORF10 mimics the Gly/N-degron motif, thereby binding competitively to CUL2
ZYG11B and inhibiting the degradation of target substrates bearing the Gly/N-degron motif.
Overall, this study sheds light on how SARS-CoV-2 ORF10 exploits the ubiquitination machinery for proteasomal degradation, and offers valuable insights for optimizing PROTAC-based drug design based on NTH CUL2
ZYG11B interaction, while pinpointing a promising target for the development of treatments for COVID-19.
Keywords: SARS-CoV-2, ORF10, Crystal structure, cullin-2 RING E3 ligase, Drug design
Graphical Abstract: available at
https://ars.els-cdn.com/content/image/1-s2.0-S2211383524001965-ga1_lrg.jpg
This paper studied a mechanism of SARS-CoV-2 ORF10 binding to CUL2
ZYG11B by mimicking Gly/N-degrons, revealing potential unique drug-targeting sites.
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The Journal of the
Institute of Materia Medica, the Chinese Academy of Medical Sciences and the
Chinese Pharmaceutical Association.
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CiteScore: 22.4
Impact Factor: 14.7 (Top 5 journal in the category of Pharmacology and pharmacy)
JIF without self-citation: 13.9
ISSN 2211-3835
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Kaixiang Zhu, Lili Song, Linyue Wang, Lei Hua, Ziyu Luo, Tongyun Wang, Bo Qin, Shuofeng Yuan, Xiaopan Gao, Wenyi Mi, Sheng Cui, SARS-CoV-2 ORF10 hijacking ubiquitination machinery reveals potential unique drug targeting sites, Acta Pharmaceutica Sinica B, Volume 14, Issue 9, 2024, Pages 4164-4173, ISSN 2211-3835,
https://doi.org/10.1016/j.apsb.2024.05.018