9AVR

Human eIF4A-1 in complex with AMP-PNP, RNA, and the inhibitor silvestrol

This is a non-PDB format compatible entry.

Summary for 9AVR

• Entry DOI: 10.2210/pdb9avr/pdb
• Descriptor: Eukaryotic initiation factor 4A-I, RNA oligonucleotide (AG)5, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (7 entities in total)
• Functional Keywords: eukaryotic initiation factor 4a-1, silvestrol inhibitor, anti-cancer, rna binding, drug, rna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 50973.89

Authors

Bhatt, G.B.,Naineni, S.K.,Cencic, R.C.,Jiramongkolsiri, E.J.,Huang, S.H.,Pelletier, J.P.,Nagar, B.N. (deposition date: 2024-03-04, release date: 2024-10-23, Last modification date: 2025-05-07)

Primary citation

Naineni, S.K.,Bhatt, G.,Jiramongkolsiri, E.,Robert, F.,Cencic, R.,Huang, S.,Nagar, B.,Pelletier, J.
Protein-RNA interactions mediated by silvestrol-insight into a unique molecular clamp.
Nucleic Acids Res., 52:12701-12711, 2024

PubMed Abstract: Molecular staples or interfacial inhibitors are small molecules that exert their activity through co-association with macromolecules leading to various effects on target functions. Some molecules inhibit target activity, while others generate gain-of-function complexes. We and others have previously identified two structurally distinct classes of molecular staples, pateamine A and rocaglates. These molecules inhibit eukaryotic initiation factor (eIF) 4A, a critical RNA helicase required for translation initiation, by simultaneously interacting with both RNA and protein components. Structural insights from members of these two families indicate that they wedge themselves between RNA bases during engagement. To extend our understanding of rocaglates, we investigated the RNA-binding properties of silvestrol, a natural rocaglate distinguished by the presence of a unique dioxanyloxy ring. Our study demonstrates that silvestrol expands the RNA-binding repertoire of rocaglates due to this structural characteristic, providing a rationale for improving synthetic molecular staples targeting eIF4A.

PubMed: 39351865
DOI: 10.1093/nar/gkae824

Experimental method

X-RAY DIFFRACTION (1.91 Å)