Fragment Screening to Identify Inhibitors Targeting Ribosome Binding of Shiga Toxin 2.

Publication Type:

Journal Article

Source:

ACS Infect Dis (2024)

Abstract:

<p>Shiga toxins are the main virulence factors of Shiga toxin producing (STEC) and . 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, , which bound at the ribosome binding site and mimicked the binding mode of the P-stalk proteins. We synthesized analogs of 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.</p>

PDB: 
8CX8 for the Stx2A1–BTB13086 complex, and 8CWQ for the Stx2A1–citrate complex
Detector: 
EIGER
Beamline: 
24-ID-E