8K9V

Crystal structure of plasmodium LysRS complexing with ASP3026 derived LysRS inhibitor 3 (ADKI3)

8K9V の概要

• エントリーDOI: 10.2210/pdb8k9v/pdb
• 分子名称: Lysine--tRNA ligase, LYSINE, ~{N}4-(2,5-dimethoxyphenyl)-~{N}2-(2-propan-2-ylsulfonylphenyl)-1,3,5-triazine-2,4-diamine, ... (5 entities in total)
• 機能のキーワード: lysyl-trna synthetase, ligase
• 由来する生物種: Plasmodium falciparum (isolate Camp / Malaysia)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 120807.74

構造登録者

Zhou, J.,Xia, M.,Yang, G.,Li, P.,Fang, P. (登録日: 2023-08-01, 公開日: 2024-06-26, 最終更新日: 2024-10-16)

主引用文献

Zhou, J.,Xia, M.,Huang, Z.,Qiao, H.,Yang, G.,Qian, Y.,Li, P.,Zhang, Z.,Gao, X.,Jiang, L.,Wang, J.,Li, W.,Fang, P.
Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors.
Commun Biol, 7:742-742, 2024

PubMed Abstract: Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of L-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.

PubMed: 38890421
DOI: 10.1038/s42003-024-06455-4

実験手法

X-RAY DIFFRACTION (1.92 Å)