8cx8
Stx2A1-BTB13086
Structural highlights
FunctionQ8XBV2_ECOLX The A subunit is responsible for inhibiting protein synthesis through the catalytic inactivation of 60S ribosomal subunits. After endocytosis, the A subunit is cleaved by furin in two fragments, A1 and A2: A1 is the catalytically active fragment, and A2 is essential for holotoxin assembly with the B subunits.[ARBA:ARBA00043904] Publication Abstract from PubMedShiga toxins are the main virulence factors of Shiga toxin producing E. coli (STEC) and S. dysenteriae. There is no effective therapy to counter the disease caused by these toxins. The A1 subunits of Shiga toxins bind the C-termini of ribosomal P-stalk proteins to depurinate the sarcin/ricin loop. The ribosome binding site of Shiga toxin 2 has not been targeted by small molecules. We screened a fragment library against the A1 subunit of Shiga toxin 2 (Stx2A1) and identified a fragment, BTB13086, which bound at the ribosome binding site and mimicked the binding mode of the P-stalk proteins. We synthesized analogs of BTB13086 and identified a series of molecules with similar affinity and inhibitory activity. These are the first compounds that bind at the ribosome binding site of Stx2A1 and inhibit activity. These compounds hold great promise for further inhibitor development against STEC infection. Fragment Screening to Identify Inhibitors Targeting Ribosome Binding of Shiga Toxin 2.,Rudolph MJ, Tsymbal AM, Dutta A, Davis SA, Algava B, Roberge JY, Tumer NE, Li XP ACS Infect Dis. 2024 Aug 9;10(8):2814-2825. doi: 10.1021/acsinfecdis.4c00224. , Epub 2024 Jun 14. PMID:38873918[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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