5S24

PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 Nsp3 macrodomain in complex with EN300-697611

5S24 の概要

• エントリーDOI: 10.2210/pdb5s24/pdb
• Group deposition: PanDDA analysis group deposition (G_1002176)
• 分子名称: Non-structural protein 3, 2-(1H-benzimidazol-1-yl)-N-methylacetamide (3 entities in total)
• 機能のキーワード: sgc - diamond i04-1 fragment screening, pandda, xchemexplorer, sars-cov-2 nsp3 macrodomain, 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: 2
• 化学式量合計: 36546.75

構造登録者

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. (登録日: 2020-11-02, 公開日: 2021-01-13, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.14 Å)