Fig. 7: Crystal structure of SARS-CoV-2 PLpro in complex with covalent inhibitor 7.
From: Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2
a Overall structure. The electron density for 7 is shown in blue mesh (Fo - Fc omit map contoured at 1.5 σ). b Interactions between binding site residues (green sticks) and 7 (cyan sticks). c Composite omit map (σ = 1.0) showing the electron density for the covalent bond between Cys111 and 7. d Superposition of selected structures highlighting the positions of the side chain of Leu162 (sticks) and the BL2 loop (cartoon) in the absence and presence of selected inhibitors: Ligand-free (PDB entry 6W9C, light green), glycerol-bound (PDB entry 6WZU, purple), GRL0617-bound (PDB entry 7CMD, light purple), and compound 7-bound (this work; cyan). Additional structures are shown in Supplementary Fig. 11. e Structural basis for selectivity toward PLpro. Superposition of 7 bound to PLpro onto human carboxy terminal hydrolase UCH-L129 (PDB entry 3KW5). The crossover loop of UCH-L1 (residues 153–157) covers the narrow groove and likely blocks the naphthylmethylamine core of 7 from binding. f Superposition of 7 bound to PLpro onto human USP431 (PDB entry 2Y6E). Severe steric clashes are present between the naphthyl ring of 7 and Phe828 and Lys838 of USP4 (light pink sticks), both of which are conserved in 80% of human USPs.
