7N3K

Oridonin-bound SARS-CoV-2 Nsp9

7N3K の概要

• エントリーDOI: 10.2210/pdb7n3k/pdb
• 分子名称: Non-structural protein 9, (1beta,6beta,7beta,8alpha,9beta,10alpha,13alpha,14R,16beta)-1,6,7,14-tetrahydroxy-7,20-epoxykauran-15-one, SULFATE ION (3 entities in total)
• 機能のキーワード: sars-cov-2, nsp9, rna binding complex, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 120056.98

構造登録者

Littler, D.R.,Gully, B.S.,Rossjohn, J. (登録日: 2021-06-01, 公開日: 2021-10-27, 最終更新日: 2024-10-16)

主引用文献

Littler, D.R.,Liu, M.,McAuley, J.L.,Lowery, S.A.,Illing, P.T.,Gully, B.S.,Purcell, A.W.,Chandrashekaran, I.R.,Perlman, S.,Purcell, D.F.J.,Quinn, R.J.,Rossjohn, J.
A natural product compound inhibits coronaviral replication in vitro by binding to the conserved Nsp9 SARS-CoV-2 protein.
J.Biol.Chem., 297:101362-101362, 2021

PubMed Abstract: The Nsp9 replicase is a conserved coronaviral protein that acts as an essential accessory component of the multi-subunit viral replication/transcription complex. Nsp9 is the predominant substrate for the essential nucleotidylation activity of Nsp12. Compounds specifically interfering with this viral activity would facilitate its study. Using a native mass-spectrometry-based approach to screen a natural product library for Nsp9 binders, we identified an ent-kaurane natural product, oridonin, capable of binding to purified SARS-CoV-2 Nsp9 with micromolar affinities. By determining the crystal structure of the Nsp9-oridonin complex, we showed that oridonin binds through a conserved site near Nsp9's C-terminal GxxxG-helix. In enzymatic assays, oridonin's binding to Nsp9 reduces its potential to act as substrate for Nsp12's Nidovirus RdRp-Associated Nucleotidyl transferase (NiRAN) domain. We also showed using in vitro cellular assays oridonin, while cytotoxic at higher doses has broad antiviral activity, reducing viral titer following infection with either SARS-CoV-2 or, to a lesser extent, MERS-CoV. Accordingly, these preliminary findings suggest that the oridonin molecular scaffold may have the potential to be developed into an antiviral compound to inhibit the function of Nsp9 during coronaviral replication.

PubMed: 34756886
DOI: 10.1016/j.jbc.2021.101362

実験手法

X-RAY DIFFRACTION (3 Å)