6URW

Crystal structure of ricin A chain in complex with inhibitor 4-(2-thienylmethyl)benzoic acid

6URW の概要

• エントリーDOI: 10.2210/pdb6urw/pdb
• 分子名称: Ricin, 1,2-ETHANEDIOL, DIMETHYL SULFOXIDE, ... (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: 31729.85

構造登録者

Harijan, R.K.,Li, X.P.,Bonanno, J.B.,Almo, S.C.,Tumer, N.E.,Schramm, V.L. (登録日: 2019-10-24, 公開日: 2020-06-17, 最終更新日: 2023-10-11)

主引用文献

Li, X.P.,Harijan, R.K.,Kahn, J.N.,Schramm, V.L.,Tumer, N.E.
Small Molecule Inhibitors Targeting the Interaction of Ricin Toxin A Subunit with Ribosomes.
Acs Infect Dis., 6:1894-1905, 2020

PubMed Abstract: Ricin toxin A subunit (RTA) removes an adenine from the universally conserved sarcin/ricin loop (SRL) on eukaryotic ribosomes, thereby inhibiting protein synthesis. No high affinity and selective small molecule therapeutic antidotes have been reported against ricin toxicity. RTA binds to the ribosomal P stalk to access the SRL. The interaction anchors RTA to the P protein C-termini at a well-defined hydrophobic pocket, which is on the opposite face relative to the active site. The RTA ribosome binding site has not been previously targeted by small molecule inhibitors. We used fragment screening with surface plasmon resonance to identify small molecular weight lead compounds that bind RTA and defined their interactions by crystallography. We identified five fragments, which bound RTA with mid-micromolar affinity. Three chemically distinct binding fragments were cocrystallized with RTA, and crystal structures were solved. Two fragments bound at the P stalk binding site, and the third bound to helix D, a motif distinct from the P stalk binding site. All fragments bound RTA remote from the catalytic site and caused little change in catalytic site geometry. Two fragments uniquely bound at the hydrophobic pocket with affinity sufficient to inhibit the catalytic activity on eukaryotic ribosomes in the low micromolar range. The binding mode of these inhibitors mimicked the interaction of the P stalk peptide, establishing that small molecule inhibitors can inhibit RTA binding to the ribosome with the potential for therapeutic intervention.

PubMed: 32428396
DOI: 10.1021/acsinfecdis.0c00127

実験手法

X-RAY DIFFRACTION (2.4 Å)