biostudies-literatureConley JFNCATS NIH HHSNIGMS NIH HHS5795-5808https://www.ebi.ac.uk/biostudies/studies/S-EPMC11840593biostudies-literatureUnknown10(6)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 ATACS omegaStructural Basis for the Improved RNA Clamping of Amidino-Rocaglates to eIF4A1.PMC11840593R35 GM118173P30 GM133893U01 TR002625Pelletier JAllen KNConley JFMcNeely JHPorco JABrown LEfalseStructural Basis for the Improved RNA Clamping of Amidino-Rocaglates to eIF4A1.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 AT2025-01-01T00:00:00Z2025 Feb2026-06-01T13:00:58.108Z2025-04-04T13:11:19.479ZS-EPMC118405933998979910.1021/acsomega.4c09421