5ZBZ

Crystal structure of the DEAD domain of Human eIF4A with sanguinarine

Summary for 5ZBZ

• Entry DOI: 10.2210/pdb5zbz/pdb
• Descriptor: Eukaryotic initiation factor 4A-I, 13-methyl[1,3]benzodioxolo[5,6-c][1,3]dioxolo[4,5-i]phenanthridin-13-ium, MALONATE ION, ... (4 entities in total)
• Functional Keywords: eukaryotic translation initiation factor 4a, sanguinarine, inhibitor, translation, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 25360.47

Authors

Ding, Y.,Ding, L. (deposition date: 2018-02-14, release date: 2019-02-20, Last modification date: 2023-11-22)

Primary citation

Jiang, C.,Tang, Y.,Ding, L.,Tan, R.,Li, X.,Lu, J.,Jiang, J.,Cui, Z.,Tang, Z.,Li, W.,Cao, Z.,Schneider-Poetsch, T.,Jiang, W.,Luo, C.,Ding, Y.,Liu, J.,Dang, Y.
Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling.
Cell Chem Biol, 26:1417-1426.e5, 2019

PubMed Abstract: DEAD-box ATP-dependent helicases (DEAH/D) are a family of conserved genes predominantly involved in gene expression regulation and RNA processing. As its prototype, eIF4AI is an essential component of the protein translation initiation complex. Utilizing a screening system based on wild-type eIF4AI and its L243G mutant with a changed linker domain, we discovered an eIF4AI inhibitor, sanguinarine (SAN) and used it to study the catalytic mechanism of eIF4AI. Herein, we describe the crystal structure of the eIF4AI-inhibitor complex and demonstrate that the binding site displays certain specificity, which can provide the basis for drug design to target eIF4AI. We report that except for competitive inhibition SAN's possible mechanism of action involves interference with eIF4AI catalytic cycling process by hindering the formation of the closed conformation of eIF4AI. In addition, our results highlight a new targetable site on eIF4AI and confirm eIF4AI as a viable pharmacological target.

PubMed: 31402318
DOI: 10.1016/j.chembiol.2019.07.010

Experimental method

X-RAY DIFFRACTION (1.30860259206 Å)