4YCV

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

Summary for 4YCV

• Entry DOI: 10.2210/pdb4ycv/pdb
• Related: 4YCU 4YCW
• Descriptor: Lysine--tRNA ligase, cladosporin (3 entities in total)
• Functional Keywords: inhibitor, complex, lysrs, cladosporin, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Plasmodium falciparum (isolate NF54)
• Total number of polymer chains: 4
• Total formula weight: 240293.84

Authors

Fang, P.,Wang, J.,Guo, M. (deposition date: 2015-02-20, release date: 2015-06-24, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.406 Å)