6M0T

Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum complexed with L-lysine and Cladosporin derivative (CL-2)

6M0T の概要

• エントリーDOI: 10.2210/pdb6m0t/pdb
• 関連するPDBエントリー: 4PG3
• 分子名称: Lysine--tRNA ligase, LYSINE, (3R)-3-[(R)-[(2R,6S)-6-methyloxan-2-yl]-oxidanyl-methyl]-6,8-bis(oxidanyl)-3,4-dihydroisochromen-1-one, ... (4 entities in total)
• 機能のキーワード: cladosporin analog, stereochemistry, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 236649.82

構造登録者

Babbar, P.,Sharma, A.,Manickam, Y. (登録日: 2020-02-22, 公開日: 2021-04-21, 最終更新日: 2024-10-23)

主引用文献

Babbar, P.,Das, P.,Manickam, Y.,Mankad, Y.,Yadav, S.,Parvez, S.,Sharma, A.,Reddy, D.S.
Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites.
Acs Infect Dis., 7:1777-1794, 2021

PubMed Abstract: Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite () lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with pharmacokinetics. Co-crystallization of the most potent compound in our series () with KRS revealed its structural basis of enzymatic binding and potency. Further, we report that has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold.

PubMed: 33843204
DOI: 10.1021/acsinfecdis.1c00092

実験手法

X-RAY DIFFRACTION (2.68 Å)