8UF5

Catalytic domain of GtfB in complex with inhibitor G43

Summary for 8UF5

• Entry DOI: 10.2210/pdb8uf5/pdb
• Related: 8FG8
• Descriptor: Glucosyltransferase-I, CALCIUM ION, N-(2-carbamoylphenyl)-5-nitro-1-benzothiophene-2-carboxamide, ... (8 entities in total)
• Functional Keywords: gtfb, gtf-i, catalytic domain, inhibitor, transferase-inhibitor complex, cell adhesion
• Biological source: Streptococcus mutans
• Total number of polymer chains: 2
• Total formula weight: 196980.93

Authors

Schormann, N.,Deivanayagam, C.,Velu, S. (deposition date: 2023-10-03, release date: 2023-10-18)

Primary citation

Zhang, Q.,Nijampatnam, B.,Hua, Z.,Nguyen, T.,Zou, J.,Cai, X.,Michalek, S.M.,Velu, S.E.,Wu, H.
Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence.
Sci Rep, 7:5974-, 2017

PubMed Abstract: 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 K against GtfB and nanomolar K 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.

PubMed: 28729722
DOI: 10.1177/00220345580370060901

Experimental method

X-RAY DIFFRACTION (2.5 Å)