4NCX

Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum 3D7

Summary for 4NCX

• Entry DOI: 10.2210/pdb4ncx/pdb
• Descriptor: Proline--tRNA ligase, 1,2-ETHANEDIOL, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: structural genomics, niaid, national institute of allergy and infectious diseases, seattle structural genomics center for infectious disease, ssgcid, ligase, prolyl-trna synthetase
• Biological source: Plasmodium falciparum 3D7
• Cellular location: Cytoplasm : Q8I5R7
• Total number of polymer chains: 2
• Total formula weight: 118451.76

Authors

Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2013-10-25, release date: 2014-10-29, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)