5FO4

Crystal structure of the P.falciparum cytosolic leucyl-tRNA synthetase editing domain (space group P1)

5FO4 の概要

• エントリーDOI: 10.2210/pdb5fo4/pdb
• 関連するPDBエントリー: 5FOC 5FOD 5FOF 5FOG 5FOL 5FOM 5FON
• 分子名称: LEUCYL TRNA SYNTHASE (2 entities in total)
• 機能のキーワード: ligase, p.falciparum, leucine-trna ligase (leurs) activity, atp + l-leucine + trna(leucine) gives amp + diphosphate + l-leucyl-trna(leucine), aminoacyl-trna synthetase, protein biosynthesis, novel boron inhibitors of leurs
• 由来する生物種: PLASMODIUM FALCIPARUM
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86705.96

構造登録者

Palencia, A.,Sonoiki, E.,Guo, D.,Ahyong, V.,Dong, C.,Li, X.,Hernandez, V.S.,Gut, J.,Legac, J.,Cooper, R.,Alley, M.R.K.,Freund, Y.R.,DeRisi, J.,Cusack, S.,Rosenthal, P.J. (登録日: 2015-11-18, 公開日: 2016-06-22, 最終更新日: 2024-05-01)

主引用文献

Sonoiki, E.,Palencia, A.,Guo, D.,Ahyong, V.,Dong, C.,Li, X.,Hernandez, V.S.,Zhang, Y.K.,Choi, W.,Gut, J.,Legac, J.,Cooper, R.,Alley, M.R.,Freund, Y.R.,Derisi, J.,Cusack, S.,Rosenthal, P.J.
Anti-Malarial Benzoxaboroles Target P. Falciparum Leucyl-tRNA Synthetase.
Antimicrob.Agents Chemother., 60:4886-, 2016

PubMed Abstract: There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.

PubMed: 27270277
DOI: 10.1128/AAC.00820-16

実験手法

X-RAY DIFFRACTION (1.85 Å)