6HCU

Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum bound to a difluoro cyclohexyl chromone ligand

6HCU の概要

• エントリーDOI: 10.2210/pdb6hcu/pdb
• 分子名称: Lysine--tRNA ligase, ~{N}-[[4,4-bis(fluoranyl)-1-oxidanyl-cyclohexyl]methyl]-6-fluoranyl-4-oxidanylidene-chromene-2-carboxamide, LYSINE, ... (7 entities in total)
• 機能のキーワード: adenylyltransferase activity, trna binding, ligase, transferase
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 119022.53

構造登録者

Tamjar, J.,Robinson, D.A.,Baragana, B.,Norcross, N.,Forte, B.,Walpole, C.,Gilbert, I.H. (登録日: 2018-08-16, 公開日: 2019-04-03, 最終更新日: 2024-10-23)

主引用文献

Baragana, B.,Forte, B.,Choi, R.,Nakazawa Hewitt, S.,Bueren-Calabuig, J.A.,Pisco, J.P.,Peet, C.,Dranow, D.M.,Robinson, D.A.,Jansen, C.,Norcross, N.R.,Vinayak, S.,Anderson, M.,Brooks, C.F.,Cooper, C.A.,Damerow, S.,Delves, M.,Dowers, K.,Duffy, J.,Edwards, T.E.,Hallyburton, I.,Horst, B.G.,Hulverson, M.A.,Ferguson, L.,Jimenez-Diaz, M.B.,Jumani, R.S.,Lorimer, D.D.,Love, M.S.,Maher, S.,Matthews, H.,McNamara, C.W.,Miller, P.,O'Neill, S.,Ojo, K.K.,Osuna-Cabello, M.,Pinto, E.,Post, J.,Riley, J.,Rottmann, M.,Sanz, L.M.,Scullion, P.,Sharma, A.,Shepherd, S.M.,Shishikura, Y.,Simeons, F.R.C.,Stebbins, E.E.,Stojanovski, L.,Straschil, U.,Tamaki, F.K.,Tamjar, J.,Torrie, L.S.,Vantaux, A.,Witkowski, B.,Wittlin, S.,Yogavel, M.,Zuccotto, F.,Angulo-Barturen, I.,Sinden, R.,Baum, J.,Gamo, F.J.,Maser, P.,Kyle, D.E.,Winzeler, E.A.,Myler, P.J.,Wyatt, P.G.,Floyd, D.,Matthews, D.,Sharma, A.,Striepen, B.,Huston, C.D.,Gray, D.W.,Fairlamb, A.H.,Pisliakov, A.V.,Walpole, C.,Read, K.D.,Van Voorhis, W.C.,Gilbert, I.H.
Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis.
Proc.Natl.Acad.Sci.USA, 116:7015-7020, 2019

PubMed Abstract: Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage and in cell-culture studies. Target deconvolution in has shown that cladosporin inhibits lysyl-tRNA synthetase (KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both KRS1 and KRS (KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between KRS1 and KRS. This series of compounds inhibit KRS and and in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for KRS1 and KRS vs. (human) KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

PubMed: 30894487
DOI: 10.1073/pnas.1814685116

実験手法

X-RAY DIFFRACTION (1.62 Å)