7qy1

X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 4

spinqualitylabelsall models 7qy1, resolution 1.45Å 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 1.45Å Ligands: CA, CL, DMS, I0W, NA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Inhibitors of the proprotein convertase furin might serve as broad-spectrum antiviral therapeutics. High cellular potency and antiviral activity against acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported for (3,5-dichlorophenyl)pyridine-derived furin inhibitors. Here we characterized the binding mechanism of this inhibitor class using structural, biophysical, and biochemical methods. We established a MALDI-TOF-MS-based furin activity assay, determined IC50 values, and solved X-ray structures of (3,5-dichlorophenyl)pyridine-derived compounds in complex with furin. The inhibitors induced a substantial conformational rearrangement of the active-site cleft by exposing a central buried tryptophan residue. These changes formed an extended hydrophobic surface patch where the 3,5-dichlorophenyl moiety of the inhibitors was inserted into a newly formed binding pocket. Consistent with these structural rearrangements, we observed slow off-rate binding kinetics and strong structural stabilization in surface plasmon resonance and differential scanning fluorimetry experiments, respectively. The discovered furin conformation offers new opportunities for structure-based drug discovery. Dichlorophenylpyridine-Based Molecules Inhibit Furin through an Induced-Fit Mechanism.,Dahms SO, Schnapp G, Winter M, Buttner FH, Schleputz M, Gnamm C, Pautsch A, Brandstetter H ACS Chem Biol. 2022 Apr 15;17(4):816-821. doi: 10.1021/acschembio.2c00103. Epub, 2022 Apr 4. PMID:35377598 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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