The accessory protein orf9b is present in both SARS-CoV-2 and SARS-CoV. Elucidating virus-host interaction at the molecular level is therefore fundamental to identify drug targets in the host. Disrupting virus-host interaction critical to the viral life-cycle represents a good strategy for drug design because it can avoid resistance commonly induced by direct-acting antiviral drugs 6– 8. They participate in a variety of virus-host interactions ranging from cell proliferation, programmed cell death, cytokine production to antiviral immunity evasion. Many studies have demonstrated the accessory proteins are critical to the virus’s survival in the host and contribute significantly to pathogenesis 4, 5. Since these proteins were believed non-essential for virus replication, they have named the accessory proteins. While SARS-CoV-2 and SARS-CoV share many proteins common in other CoVs, including 4 major structural proteins (S, E, M, and N proteins) and 16 nonstructural proteins (nsp1-16), they possess a unique set of proteins, namely orf3a, 3b, 6, 7a, 7b, 8a, 8b, and 9b 3, 4. The International Committee on Taxonomy of Viruses (ICTV) officially named the causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), based on its similarity to SARS-CoV 2. The global economy is experiencing the worst plunge in recent history amid fears of further deterioration of the COVID-19 situation. Despite scientists worldwide racing to develop antiviral drugs, curative treatments are unavailable at the time of writing. The ongoing Coronavirus Disease 2019 (COVID-19) pandemic has caused a Once-in-a-Century global crisis 1. Our findings shed light on the mechanism underlying SARS-CoV-2 orf9b mediated suppression of interferon responses. Strikingly, the binding affinity of Hsp90 EEVD motif to TOM70 NTD is reduced by ~29-fold when orf9b occupies the pocket of TOM70 CTD, supporting the hypothesis that orf9b allosterically inhibits the Hsp90/TOM70 interaction. While the interaction between C-peptide and TOM70 CTD is an endothermic process, the interaction between Hsp90 EEVD and TOM70 NTD is exothermic, which underscores the distinct binding mechanisms at NTD and CTD pockets. Using isothermal titration calorimetry (ITC), we demonstrated that the orf9b dimer does not bind TOM70, but a synthetic peptide harboring a segment of orf9b (denoted C-peptide) binds TOM70 with nanomolar K D. Interactions between orf9b and TOM70 CTD are primarily hydrophobic and distinct from the electrostatic interaction between the heat shock protein 90 (Hsp90) EEVD motif and the TOM70 N-terminal domain (NTD). A central portion of orf9b occupies the deep pocket in the TOM70 C-terminal domain (CTD) and adopts a helical conformation strikingly different from the β-sheet-rich structure of the orf9b homodimer. Here, we determined the crystal structure of SARS-CoV-2 orf9b in complex with the cytosolic segment of human TOM70 to 2.2 Å.
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It is implicated in immune evasion by targeting mitochondria, where it associates with the versatile adapter TOM70. Orf9b is a unique accessory protein of SARS-CoV-2 and SARS-CoV. Although the accessory proteins are considered non-essential for coronavirus replication, accumulating evidences demonstrate they are critical to virus-host interaction and pathogenesis.