biostudies-literatureUnknown14(9)Zhu KNational Natural Science Foundation of ChinaViruses 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. Here, we 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<suActa pharmaceutica Sinica. B4164-4173https://www.ebi.ac.uk/biostudies/studies/S-EPMC11413682biostudies-literatureSARS-CoV-2 ORF10 hijacking ubiquitination machinery reveals potential unique drug targeting sites.PMC11413682Song LYuan SLuo ZZhu KWang TMi WGao XCui SHua LQin BWang LfalseSARS-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. Here, we 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<su2024-01-01T00:00:00Z2024 Sep2026-06-01T19:28:58.464Z2025-04-04T02:19:21.195ZS-EPMC114136823930949910.1016/j.apsb.2024.05.018