6XB7

IRES-targeting Small Molecule Inhibits Enterovirus 71 Replication via Allosteric Stabilization of a Ternary Complex

6XB7 の概要

• エントリーDOI: 10.2210/pdb6xb7/pdb
• NMR情報: BMRB: 50268
• 分子名称: RNA (41-MER), 3-amino-N-(diaminomethylidene)-5-(dimethylamino)-6-(phenylethynyl)pyrazine-2-carboxamide (2 entities in total)
• 機能のキーワード: rna-small molecule complex, rna binding protein, rna
• 由来する生物種: Enterovirus A71
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13464.21

構造登録者

Tolbert, B.S.,Davila, J.,Sugarman, A.L.,Chiu, L.Y. (登録日: 2020-06-05, 公開日: 2020-09-02, 最終更新日: 2024-05-01)

主引用文献

Davila-Calderon, J.,Patwardhan, N.N.,Chiu, L.Y.,Sugarman, A.,Cai, Z.,Penutmutchu, S.R.,Li, M.L.,Brewer, G.,Hargrove, A.E.,Tolbert, B.S.
IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex.
Nat Commun, 11:4775-4775, 2020

PubMed Abstract: Enterovirus 71 (EV71) poses serious threats to human health, particularly in Southeast Asia, and no drugs or vaccines are available. Previous work identified the stem loop II structure of the EV71 internal ribosomal entry site as vital to viral translation and a potential target. After screening an RNA-biased library using a peptide-displacement assay, we identify DMA-135 as a dose-dependent inhibitor of viral translation and replication with no significant toxicity in cell-based studies. Structural, biophysical, and biochemical characterization support an allosteric mechanism in which DMA-135 induces a conformational change in the RNA structure that stabilizes a ternary complex with the AUF1 protein, thus repressing translation. This mechanism is supported by pull-down experiments in cell culture. These detailed studies establish enterovirus RNA structures as promising drug targets while revealing an approach and mechanism of action that should be broadly applicable to functional RNA targeting.

PubMed: 32963221
DOI: 10.1038/s41467-020-18594-3

実験手法

SOLUTION NMR