7XC4

Crystal structure of SARS-CoV-2 NSP3 Macrodomain 3 (SARS-unique domain-M) in complex with Oxaprozin

7XC4 の概要

• エントリーDOI: 10.2210/pdb7xc4/pdb
• 分子名称: Papain-like protease nsp3, 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid (3 entities in total)
• 機能のキーワード: g-quadruplex-binding, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29419.67

構造登録者

Li, J.,Liu, Y.,Gao, J.,Ruan, K. (登録日: 2022-03-22, 公開日: 2022-11-23, 最終更新日: 2023-11-29)

主引用文献

Li, J.,Zhong, F.,Li, M.,Liu, Y.,Wang, L.,Liu, M.,Li, F.,Zhang, J.,Wu, J.,Shi, Y.,Zhang, Z.,Tu, X.,Ruan, K.,Gao, J.
Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen.
J.Med.Chem., 65:15227-15237, 2022

PubMed Abstract: Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore a potential therapeutic target. Here, we solved the crystal structure of SARS-CoV-2 Mac3, which reveals a small-molecule binding pocket. Two low-molecular-weight drugs, oxaprozin and meclomen, induced different patterns of nuclear magnetic resonance (NMR) chemical shift perturbations (CSPs). Meclomen binds to site I of SARS-CoV-2 Mac3 with binding pose determined by NMR CSP and transferred paramagnetic relaxation enhancement, while oxaprozin binds to site II as revealed by the crystal structure. Interestingly, oxaprozin and meclomen both perturb residues in site I of SARS-CoV Mac3. Fluorescence polarization experiments further demonstrated that oxaprozin and meclomen inhibited the binding of DNA-G4s to SARS-CoV-2 Mac3. Our work identified two adjacent ligand-binding sites of SARS-CoV-2 Mac3 that shall facilitate structure-guided fragment linking of these compounds for more potent inhibitors.

PubMed: 36356292
DOI: 10.1021/acs.jmedchem.2c01168

実験手法

X-RAY DIFFRACTION (2.1 Å)