8uf5

Catalytic domain of GtfB in complex with inhibitor G43Catalytic domain of GtfB in complex with inhibitor G43

Structural highlights 8uf5 is a 2 chain structure with sequence from Streptococcus mutans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: , , , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GTFB_STRMU Production of extracellular glucans, that are thought to play a key role in the development of the dental plaque because of their ability to adhere to smooth surfaces and mediate the aggregation of bacterial cells and food debris. Publication Abstract from PubMed Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in silico against the available crystal structure of the GtfC catalytic domain. Based on the predicted binding affinities and drug-like properties, small molecules were selected and evaluated for their ability to reduce S. mutans biofilms, as well as inhibit the activity of Gtfs. The most potent inhibitor was further characterized for Gtf binding using OctetRed instrument, which yielded low micromolar KD against GtfB and nanomolar KD against GtfC, demonstrating selectivity towards GtfC. Additionally, the lead compound did not affect the overall growth of S. mutans and commensal oral bacteria, and selectively inhibit the biofilm formation by S. mutans, indicative of its selectivity and non-bactericidal nature. The lead compound also effectively reduced cariogenicity in vivo in a rat model of dental caries. An analog that docked poorly in the GtfC catalytic domain failed to inhibit the activity of Gtfs and S. mutans biofilms, signifying the specificity of the lead compound. This report illustrates the validity and potential of structure-based design of anti-S. mutans virulence inhibitors. Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence.,Zhang Q, Nijampatnam B, Hua Z, Nguyen T, Zou J, Cai X, Michalek SM, Velu SE, Wu H Sci Rep. 2017 Jul 20;7(1):5974. doi: 10.1038/s41598-017-06168-1. PMID:28729722 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 8uf5, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image