9DTS

Crystal structure of the human eIF4A1/AMPPNP/amidino-rocaglate/polypurine RNA complex

これはPDB形式変換不可エントリーです。

9DTS の概要

• エントリーDOI: 10.2210/pdb9dts/pdb
• 分子名称: Eukaryotic initiation factor 4A-I, RNA (5'-R(P*AP*GP*AP*GP*AP*GP*AP*G)-3'), MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: rna helicase, dead box helicase, rocaglate, protein-rna complex, translation, hydrolase-rna complex, hydrolase/rna
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 194595.92

構造登録者

Conley, J.F.,Allen, K.N. (登録日: 2024-10-01, 公開日: 2025-03-12)

主引用文献

Conley, J.F.,Brown, L.E.,McNeely, J.H.,Pelletier, J.,Porco Jr., J.A.,Allen, K.N.
Structural Basis for the Improved RNA Clamping of Amidino-Rocaglates to eIF4A1.
Acs Omega, 10:5795-5808, 2025

PubMed Abstract: Eukaryotic initiation factor 4A-1 (eIF4A1) is an ATP-dependent RNA helicase that unwinds 5'-UTR mRNA secondary structures to facilitate cap-dependent translation initiation. Rocaglates, a class of natural products typified by rocaglamide A (RocA), possess antineoplastic and anti-infectious activity mediated by their interaction with eIF4A1. Rocaglates inhibit cap-dependent translation initiation by "clamping" eIF4A1 onto polypurine RNA, which impedes ribosome scanning. A novel class of rocaglate derivatives, amidino-rocaglates (ADRs) which feature an amidine ring fused to the rocaglate core, is particularly effective at promoting eIF4A1-RNA-clamping compared to other rocaglate congeners. Herein, we present the X-ray crystal structure of an ADR in complex with eIF4A1, the nonhydrolyzable ATP ground-state mimic adenylyl-imidodiphosphate (AMPPNP), and poly r(AG) RNA refined to 1.69 Å resolution. The binding pose and interactions of the ADR with eIF4A1 do not differ substantially from those of RocA, prompting an investigation of the basis for enhanced target engagement. Computational modeling suggests that the rigidified ADR scaffold is inherently preorganized in an eIF4A1-RNA binding-competent conformation, thereby avoiding entropic penalties associated with RocA binding. This study illustrates how conformational rigidification of the rocaglate scaffold can be leveraged to improve potency for the development of rocaglates as potential anticancer and anti-infectious agents.

PubMed: 39989799
DOI: 10.1021/acsomega.4c09421

実験手法

X-RAY DIFFRACTION (1.69 Å)