4YCV

Crystal structure of cladosporin in complex with plasmodium lysyl-tRNA synthetase

4YCV の概要

• エントリーDOI: 10.2210/pdb4ycv/pdb
• 関連するPDBエントリー: 4YCU 4YCW
• 分子名称: Lysine--tRNA ligase, cladosporin (3 entities in total)
• 機能のキーワード: inhibitor, complex, lysrs, cladosporin, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Plasmodium falciparum (isolate NF54)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 240293.84

構造登録者

Fang, P.,Wang, J.,Guo, M. (登録日: 2015-02-20, 公開日: 2015-06-24, 最終更新日: 2024-11-13)

主引用文献

Fang, P.,Han, H.,Wang, J.,Chen, K.,Chen, X.,Guo, M.
Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor.
Chem.Biol., 22:734-744, 2015

PubMed Abstract: Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits Plasmodium falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report three crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all three structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydropyran moiety of cladosporin are critical for the specificity of cladosporin against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure-driven drug development.

PubMed: 26074468
DOI: 10.1016/j.chembiol.2015.05.007

実験手法

X-RAY DIFFRACTION (3.406 Å)