7ROR

Plasmodium falciparum tyrosyl-tRNA synthetase in complex with tyrosine-AMP

7ROR の概要

• エントリーDOI: 10.2210/pdb7ror/pdb
• 分子名称: Tyrosine--tRNA ligase, 5'-O-[(S)-{[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]oxy}(hydroxy)phosphoryl]adenosine, MALONATE ION, ... (6 entities in total)
• 機能のキーワード: enzyme, tyrosyl-trna synthetase, malaria, inhibitor, ligase, tyrosine-amp
• 由来する生物種: Plasmodium falciparum (isolate 3D7)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88679.90

構造登録者

Metcalfe, R.D.,Xie, S.C.,Morton, C.J.,Tilley, L.,Griffin, M.D.W. (登録日: 2021-08-02, 公開日: 2022-06-08, 最終更新日: 2023-10-18)

主引用文献

Xie, S.C.,Metcalfe, R.D.,Dunn, E.,Morton, C.J.,Huang, S.C.,Puhalovich, T.,Du, Y.,Wittlin, S.,Nie, S.,Luth, M.R.,Ma, L.,Kim, M.S.,Pasaje, C.F.A.,Kumpornsin, K.,Giannangelo, C.,Houghton, F.J.,Churchyard, A.,Famodimu, M.T.,Barry, D.C.,Gillett, D.L.,Dey, S.,Kosasih, C.C.,Newman, W.,Niles, J.C.,Lee, M.C.S.,Baum, J.,Ottilie, S.,Winzeler, E.A.,Creek, D.J.,Williamson, N.,Parker, M.W.,Brand, S.,Langston, S.P.,Dick, L.R.,Griffin, M.D.W.,Gould, A.E.,Tilley, L.
Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.
Science, 376:1074-1079, 2022

PubMed Abstract: Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite , namely tyrosine RS (YRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

PubMed: 35653481
DOI: 10.1126/science.abn0611

実験手法

X-RAY DIFFRACTION (1.8 Å)