7XC3

Crystal structure of SARS-CoV-2 NSP3 Macrodomain 3 (SARS-unique domain-M)

Summary for 7XC3

• Entry DOI: 10.2210/pdb7xc3/pdb
• Descriptor: Papain-like protease nsp3 (2 entities in total)
• Functional Keywords: g-quadruplex-binding macrodomain, sars-unique domain, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 28484.72

Authors

Li, J.,Gao, J. (deposition date: 2022-03-22, release date: 2022-11-23, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.7 Å)