5FOL

Crystal structure of the Cryptosporidium muris cytosolic leucyl-tRNA synthetase editing domain complex with a post-transfer editing analogue of isoeucine (Ile2AA)

5FOL の概要

• エントリーDOI: 10.2210/pdb5fol/pdb
• 分子名称: LEUCYL-TRNA SYNTHETASE, PHOSPHATE ION, 2'-(L-ISOLEUCYL)AMINO-2'-DEOXYADENOSINE, ... (4 entities in total)
• 機能のキーワード: lyase, leucine-trna ligase (leurs) activity, atp + l-leucine + trna(leucine) give amp + diphosphate + l-leucyl-trna(leucine), post-transfer editing activity of leurs, aminoacyl-trna synthetase, protein biosynthesis, novel boron inhibitors of the editing site of leurs
• 由来する生物種: CRYPTOSPORIDIUM MURIS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33485.58

構造登録者

Palencia, A.,Liu, R.J.,Lukarska, M.,Gut, J.,Bougdour, A.,Touquet, B.,Wang, E.D.,Alley, M.R.K.,Rosenthal, P.J.,Hakimi, M.A.,Cusack, S. (登録日: 2015-11-24, 公開日: 2016-08-03, 最終更新日: 2024-01-10)

主引用文献

Palencia, A.,Liu, R.,Lukarska, M.,Gut, J.,Bougdour, A.,Touquet, B.,Wang, E.,Li, X.,Alley, M.R.K.,Freund, Y.R.,Rosenthal, P.J.,Hakimi, M.,Cusack, S.
Cryptosporidium and Toxoplasma Parasites are Inhibited by a Benzoxaborole Targeting Leucyl-tRNA Synthetase.
Antimicrob.Agents Chemother., 60:5817-, 2016

PubMed Abstract: The apicomplexan parasites Cryptosporidium and Toxoplasma are serious threats to human health. Cryptosporidiosis is a severe diarrheal disease in malnourished children and immunocompromised individuals, with the only FDA-approved drug treatment currently being nitazoxanide. The existing therapies for toxoplasmosis, an important pathology in immunocompromised individuals and pregnant women, also have serious limitations. With the aim of developing alternative therapeutic options to address these health problems, we tested a number of benzoxaboroles, boron-containing compounds shown to be active against various infectious agents, for inhibition of the growth of Cryptosporidium parasites in mammalian cells. A 3-aminomethyl benzoxaborole, AN6426, with activity in the micromolar range and with activity comparable to that of nitazoxanide, was identified and further characterized using biophysical measurements of affinity and crystal structures of complexes with the editing domain of Cryptosporidium leucyl-tRNA synthetase (LeuRS). The same compound was shown to be active against Toxoplasma parasites, with the activity being enhanced in the presence of norvaline, an amino acid that can be mischarged by LeuRS. Our observations are consistent with AN6426 inhibiting protein synthesis in both Cryptosporidium and Toxoplasma by forming a covalent adduct with tRNA(Leu) in the LeuRS editing active site and suggest that further exploitation of the benzoxaborole scaffold is a valid strategy to develop novel, much needed antiparasitic agents.

PubMed: 27431220
DOI: 10.1128/AAC.00873-16

実験手法

X-RAY DIFFRACTION (1.77 Å)