4Q15

Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with Halofuginone and AMPPNP in space group P212121 at 2.35 A

4Q15 の概要

• エントリーDOI: 10.2210/pdb4q15/pdb
• 関連するPDBエントリー: 4NCX 4OLF
• 分子名称: Proline--tRNA ligase, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (6 entities in total)
• 機能のキーワード: structural genomics, niaid, national institute of allergy and infectious diseases, seattle structural genomics center for infectious disease, ssgcid, prolyl-trna synthetase, ligase
• 由来する生物種: Plasmodium falciparum
• 細胞内の位置: Cytoplasm : Q8I5R7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 120049.56

構造登録者

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (登録日: 2014-04-02, 公開日: 2016-04-20, 最終更新日: 2024-11-27)

主引用文献

Hewitt, S.N.,Dranow, D.M.,Horst, B.G.,Abendroth, J.A.,Forte, B.,Hallyburton, I.,Jansen, C.,Baragana, B.,Choi, R.,Rivas, K.L.,Hulverson, M.A.,Dumais, M.,Edwards, T.E.,Lorimer, D.D.,Fairlamb, A.H.,Gray, D.W.,Read, K.D.,Lehane, A.M.,Kirk, K.,Myler, P.J.,Wernimont, A.,Walpole, C.,Stacy, R.,Barrett, L.K.,Gilbert, I.H.,Van Voorhis, W.C.
Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase.
Acs Infect Dis., 3:34-44, 2017

PubMed Abstract: Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit PfProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of PfProRS. We identified two new inhibitors of PfProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with PfProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.

PubMed: 27798837
DOI: 10.1021/acsinfecdis.6b00078

実験手法

X-RAY DIFFRACTION (2.35 Å)