1H,13C and 15N chemical shift assignments of the SUD domains of SARS-CoV-2 non-structural protein 3c: “The SUD-M and SUD-C domains”

Gallo, Angelo; Tsika, Aikaterini C.; Fourkiotis, Nikolaos K; Cantini, Francesca; Banci, Lucia; Sreeramulu, Sridhar; Schwalbe, Harald; Spyroulias, Georgios A.

doi:10.1007/s12104-020-10000-9

Cited by 5 publications

(6 citation statements)

References 18 publications

(22 reference statements)

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“…15 Here, we screened a library of 540 investigational or approved drugs with molecular weight less than 350 Da using protein-observed NMR chemical shift 27,29 To enhance the throughput, each cocktail containing 10 compounds was titrated to 15 N-labeled SARS-CoV-2 Mac3 at a ligand/protein molar ratio of 4:1 (Figure 1d). The cocktail that induced significant CSPs 19 was deconvoluted by titrating each individual component. Two drugs, oxaprozin and meclomen, were thus identified with a weak binding affinity of 1.2 and 0.9 mM, respectively (Figure S2a,b).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Chemical shift assignments were retrieved from those previously deposited in the Biological Magnetic Resonance Data Bank: SARS-CoV-2 Mac3 (BMRB Entry 50516) 19 and SARS-CoV Mac3 (BMRB Entry 15469). 46 Crystallization, Data Collection, and Structure Determination.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…16−18 SARS-CoV-2 Mac3 shares 81% sequence identity with SARS-CoV (Figure S1a), implying that they have similar biochemical functions. 19 SARS-CoV-2 and SARS-CoV Mac3 bind oligo(G)-nucleotides (both ribonucleotides and deoxynucleotides) capable of forming G-quadruplexes (G4s). 17,20,21 SARS-CoV Mac3 is essential for the activity of the viral replication/transcription complex, which is abrogated by mutagenesis of charged amino acid residues of SARS-CoV Mac3, which are considered to be involved in G-quadruplex-binding.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Macrodomain 3 (Mac3) in the nonstructural protein 3 (Figure a) of SARS-CoV-2 is of particular interest as Mac3 is present in only three highly pathogenic human coronaviruses: SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome-coronavirus. − SARS-CoV-2 Mac3 shares 81% sequence identity with SARS-CoV (Figure S1a), implying that they have similar biochemical functions . SARS-CoV-2 and SARS-CoV Mac3 bind oligo(G)-nucleotides (both ribonucleotides and deoxynucleotides) capable of forming G-quadruplexes (G4s). ,, SARS-CoV Mac3 is essential for the activity of the viral replication/transcription complex, which is abrogated by mutagenesis of charged amino acid residues of SARS-CoV Mac3, which are considered to be involved in G-quadruplex-binding .…”

Section: Introductionmentioning

confidence: 99%

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Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen

Zhong

et al. 2022

J. Med. Chem.

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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.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen

Zhong

et al. 2022

J. Med. Chem.

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“…NMR has proven key structural assignments ( 1 H, 13 C, 15 N) included SARS Unique Domains; SUD-M, SUD-C ( Gallo et al, 2021b ) and Nsp3 ( Korn et al, 2020 ). The C-terminal dimerization domain of SARS-CoV-2 nucleocapsid protein provides a basis for downstream purposes, particularly site-resolved drug binding.…”

Section: Nuclear Magnetic Resonance (Nmr) Spectroscopymentioning

confidence: 99%

NMR spectroscopy spotlighting immunogenicity induced by COVID-19 vaccination to mitigate future health concerns

Ali

Nedvědová

Badshah

et al. 2022

Current Research in Immunology

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SARS‐CoV‐2‐encoded inhibitors of human LINE‐1 retrotransposition

Yang

Shen

et al. 2022

Journal of Medical Virology

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The ongoing pandemic of severe acute respiratory coronavirus 2 (SARS‐CoV‐2) is causing a devastating impact on public health worldwide. However, details concerning the profound impact of SARS‐CoV‐2 on host cells remain elusive. Here, we investigated the effects of SARS‐CoV‐2‐encoded viral proteins on the intracellular activity of long interspersed element 1 (L1) retrotransposons using well‐established reporter systems. Several nonstructural or accessory proteins (Nsps) of SARS‐CoV‐2 (i.e., Nsp1, Nsp3, Nsp5, and Nsp14) significantly suppress human L1 mobility, and these viral L1 inhibitors generate a complex network that modulates L1 transposition. Specifically, Nsp1 and Nsp14 inhibit the intracellular accumulation of L1 open reading frame proteins (ORF1p), whereas Nsp3, Nsp5, and Nsp14 repress the reverse transcriptase activity of L1 ORF2p. Given recent findings concerning the roles of L1 in antiviral immune activation and host genome instability, the anti‐L1 activities mediated by SARS‐CoV‐2‐encoded inhibitors suggest that SARS‐CoV‐2 employs different strategies to optimize the host genetic environment.

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1H,13C and 15N chemical shift assignments of the SUD domains of SARS-CoV-2 non-structural protein 3c: “The SUD-M and SUD-C domains”

Cited by 5 publications

References 18 publications

Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen

Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen

NMR spectroscopy spotlighting immunogenicity induced by COVID-19 vaccination to mitigate future health concerns

SARS‐CoV‐2‐encoded inhibitors of human LINE‐1 retrotransposition

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