7p51

CRYSTAL STRUCTURE OF THE SARS-COV-2 MAIN PROTEASE COMPLEXED WITH FRAGMENT F01

spinqualitylabelsall models 7p51, resolution 1.47Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.474Å Ligands: 5P9, CSO, DMS, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The main protease (3CLp) of the SARS-CoV-2, the causative agent for the COVID-19 pandemic, is one of the main targets for drug development. To be active, 3CLp relies on a complex interplay between dimerization, active site flexibility, and allosteric regulation. The deciphering of these mechanisms is a crucial step to enable the search for inhibitors. In this context, using NMR spectroscopy, we studied the conformation of dimeric 3CLp from the SARS-CoV-2 and monitored ligand binding, based on NMR signal assignments. We performed a fragment-based screening that led to the identification of 38 fragment hits. Their binding sites showed three hotspots on 3CLp, two in the substrate binding pocket and one at the dimer interface. F01 is a non-covalent inhibitor of the 3CLp and has antiviral activity in SARS-CoV-2 infected cells. This study sheds light on the complex structure-function relationships of 3CLp, and constitutes a strong basis to assist in developing potent 3CLp inhibitors. NMR spectroscopy of the main protease of SARS-CoV-2 and fragment-based screening identify three protein hotspots and an antiviral fragment.,Cantrelle FX, Boll E, Brier L, Moschidi D, Belouzard S, Landry V, Leroux F, Dewitte F, Landrieu I, Dubuisson J, Deprez B, Charton J, Hanoulle X Angew Chem Int Ed Engl. 2021 Sep 27. doi: 10.1002/anie.202109965. PMID:34570415 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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