6XKI

Crystal structure of eIF4A-I in complex with RNA bound to des-MePateA, a pateamine A analog

Summary for 6XKI

• Entry DOI: 10.2210/pdb6xki/pdb
• Descriptor: Eukaryotic initiation factor 4A-I, RNA (5'-R(*AP*GP*AP*GP*AP*GP*AP*GP*AP*G)-3'), PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (6 entities in total)
• Functional Keywords: inhibitor, rna, translation initiation, translation, translation-rna-inhibitor complex, translation/rna/inhibitor
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 48740.24

Authors

Liang, J.,Naineni, S.K.,Pelletier, J.,Nagar, B. (deposition date: 2020-06-26, release date: 2021-01-06, Last modification date: 2023-10-18)

Primary citation

Naineni, S.K.,Liang, J.,Hull, K.,Cencic, R.,Zhu, M.,Northcote, P.,Teesdale-Spittle, P.,Romo, D.,Nagar, B.,Pelletier, J.
Functional mimicry revealed by the crystal structure of an eIF4A:RNA complex bound to the interfacial inhibitor, desmethyl pateamine A.
Cell Chem Biol, 28:825-, 2021

PubMed Abstract: Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of an eIF4A1:RNA complex bound to an analog of the marine sponge-derived natural product PatA, C5-desmethyl PatA (DMPatA). One end of this small molecule wedges itself between two RNA bases while the other end is cradled by several protein residues. Strikingly, DMPatA interacts with the eIF4A1:RNA complex in an almost identical fashion as rocaglamide A (RocA), despite being completely unrelated from a structural standpoint. The structural data rationalize the ability of PatA analogs to target a wider range of RNA substrates compared to RocA. We define the molecular basis of how DMPatA is able to clamp eIF4A1 onto RNA, imparting potent inhibitory properties to this molecule.

PubMed: 33412110
DOI: 10.1016/j.chembiol.2020.12.006

Experimental method

X-RAY DIFFRACTION (2.87 Å)