8TAD

RTA in complex with inhibitor RUNT-206

8TAD の概要

• エントリーDOI: 10.2210/pdb8tad/pdb
• 分子名称: Ricin A chain, (9aM)-5,5-dimethyl-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylic acid, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: n-glycosidase, inhibitor, toxin, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Ricinus communis (castor bean)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29372.57

構造登録者

Rudolph, M.J.,Tumer, N. (登録日: 2023-06-27, 公開日: 2024-05-01)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.76 Å)