4WI1

Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with TCMDC-124506

Summary for 4WI1

• Entry DOI: 10.2210/pdb4wi1/pdb
• Related: 4NCX 4OLF 4Q15
• Descriptor: Proline--tRNA ligase, 1-(4-fluorophenyl)-3-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: ssgcid, plasmodium falciparum, prolyl-trna synthetase, prors, proline--trna ligase, structural genomics, seattle structural genomics center for infectious disease, ligase
• Biological source: Plasmodium falciparum
• Cellular location: Cytoplasm : Q8I5R7
• Total number of polymer chains: 2
• Total formula weight: 119832.50

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2014-09-25, release date: 2016-05-04, Last modification date: 2023-09-27)

Primary citation

Nakazawa Hewitt, S.,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.S.,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., 2016

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

Experimental method

X-RAY DIFFRACTION (1.65 Å)