8T9V

RTA-RUNT-59 complex structure

Summary for 8T9V

• Entry DOI: 10.2210/pdb8t9v/pdb
• Descriptor: Ricin, (9aP)-7-fluoro-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylic acid, NONAETHYLENE GLYCOL, ... (4 entities in total)
• Functional Keywords: n-glycosidase, inhibitors, toxin
• Biological source: Ricinus communis (castor bean)
• Total number of polymer chains: 1
• Total formula weight: 29598.39

Authors

Rudolph, M.J.,Tumer, N. (deposition date: 2023-06-26, release date: 2024-05-01, Last modification date: 2024-11-13)

Primary citation

Rudolph, M.J.,Dutta, A.,Tsymbal, A.M.,McLaughlin, J.E.,Chen, Y.,Davis, S.A.,Theodorous, S.A.,Pierce, M.,Algava, B.,Zhang, X.,Szekely, Z.,Roberge, J.Y.,Li, X.P.,Tumer, N.E.
Structure-based design and optimization of a new class of small molecule inhibitors targeting the P-stalk binding pocket of ricin.
Bioorg.Med.Chem., 100:117614-117614, 2024

PubMed Abstract: Ricin, a category-B agent for bioterrorism, and Shiga toxins (Stxs), which cause food poisoning bind to the ribosomal P-stalk to depurinate the sarcin/ricin loop. No effective therapy exists for ricin or Stx intoxication. Ribosome binding sites of the toxins have not been targeted by small molecules. We previously identified CC10501, which inhibits toxin activity by binding the P-stalk pocket of ricin toxin A subunit (RTA) remote from the catalytic site. Here, we developed a fluorescence polarization assay and identified a new class of compounds, which bind P-stalk pocket of RTA with higher affinity and inhibit catalytic activity with submicromolar potency. A lead compound, RU-NT-206, bound P-stalk pocket of RTA with similar affinity as a five-fold larger P-stalk peptide and protected cells against ricin and Stx2 holotoxins for the first time. These results validate the P-stalk binding site of RTA as a critical target for allosteric inhibition of the active site.

PubMed: 38340640
DOI: 10.1016/j.bmc.2024.117614

Experimental method

X-RAY DIFFRACTION (1.945 Å)