7MLP

Crystal structure of ricin A chain in complex with 5-(2,6-dimethylphenyl)thiophene-2-carboxylic acid

7MLP の概要

• エントリーDOI: 10.2210/pdb7mlp/pdb
• 分子名称: Ricin, 5-(2,6-dimethylphenyl)thiophene-2-carboxylic acid, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: ricin chain-a, rta, hydrolase, toxin, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/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: 30803.48

構造登録者

Harijan, R.K.,Li, X.P.,Cao, B.,Augeri, D.,Bonanno, J.B.,Almo, S.C.,Tumer, N.E.,Schramm, V.L. (登録日: 2021-04-28, 公開日: 2022-02-09, 最終更新日: 2023-10-18)

主引用文献

Li, X.P.,Harijan, R.K.,Cao, B.,Kahn, J.N.,Pierce, M.,Tsymbal, A.M.,Roberge, J.Y.,Augeri, D.,Tumer, N.E.
Synthesis and Structural Characterization of Ricin Inhibitors Targeting Ribosome Binding Using Fragment-Based Methods and Structure-Based Design.
J.Med.Chem., 64:15334-15348, 2021

PubMed Abstract: Ricin toxin A subunit (RTA) is the catalytic subunit of ricin, which depurinates an adenine from the sarcin/ricin loop in eukaryotic ribosomes. There are no approved inhibitors against ricin. We used a new strategy to disrupt RTA-ribosome interactions by fragment screening using surface plasmon resonance. Here, using a structure-guided approach, we improved the affinity and inhibitory activity of small-molecular-weight lead compounds and obtained improved compounds with over an order of magnitude higher efficiency. Four advanced compounds were characterized by X-ray crystallography. They bind at the RTA-ribosome binding site as the original compound but in a distinctive manner. These inhibitors bind remotely from the catalytic site and cause local conformational changes with no alteration of the catalytic site geometry. Yet they inhibit depurination by ricin holotoxin and inhibit the cytotoxicity of ricin in mammalian cells. They are the first agents that protect against ricin holotoxin by acting directly on RTA.

PubMed: 34648707
DOI: 10.1021/acs.jmedchem.1c01370

実験手法

X-RAY DIFFRACTION (1.78 Å)