5S2H

PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 Nsp3 macrodomain in complex with Z2856434920

Summary for 5S2H

• Entry DOI: 10.2210/pdb5s2h/pdb
• Group deposition: PanDDA analysis group deposition (G_1002175)
• Descriptor: Non-structural protein 3, ethyl (1,1-dioxo-1lambda~6~,4-thiazinan-4-yl)acetate (3 entities in total)
• Functional Keywords: sgc - diamond i04-1 fragment screening, pandda, xchemexplorer, sars-cov-2 nsp3 macrodomain, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 36578.81

Authors

Fearon, D.,Schuller, M.,Rangel, V.L.,Douangamath, A.,Rack, J.G.M.,Zhu, K.,Aimon, A.,Brandao-Neto, J.,Dias, A.,Dunnet, L.,Gorrie-Stone, T.J.,Powell, A.J.,Krojer, T.,Skyner, R.,Thompson, W.,Ahel, I.,von Delft, F. (deposition date: 2020-11-02, release date: 2021-01-13, Last modification date: 2024-03-06)

Primary citation

Schuller, M.,Correy, G.J.,Gahbauer, S.,Fearon, D.,Wu, T.,Diaz, R.E.,Young, I.D.,Carvalho Martins, L.,Smith, D.H.,Schulze-Gahmen, U.,Owens, T.W.,Deshpande, I.,Merz, G.E.,Thwin, A.C.,Biel, J.T.,Peters, J.K.,Moritz, M.,Herrera, N.,Kratochvil, H.T.,Aimon, A.,Bennett, J.M.,Brandao Neto, J.,Cohen, A.E.,Dias, A.,Douangamath, A.,Dunnett, L.,Fedorov, O.,Ferla, M.P.,Fuchs, M.R.,Gorrie-Stone, T.J.,Holton, J.M.,Johnson, M.G.,Krojer, T.,Meigs, G.,Powell, A.J.,Rack, J.G.M.,Rangel, V.L.,Russi, S.,Skyner, R.E.,Smith, C.A.,Soares, A.S.,Wierman, J.L.,Zhu, K.,O'Brien, P.,Jura, N.,Ashworth, A.,Irwin, J.J.,Thompson, M.C.,Gestwicki, J.E.,von Delft, F.,Shoichet, B.K.,Fraser, J.S.,Ahel, I.
Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.
Sci Adv, 7:-, 2021

PubMed Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

PubMed: 33853786
DOI: 10.1126/sciadv.abf8711

Experimental method

X-RAY DIFFRACTION (1.068 Å)