9R32
CRYSTAL STRUCTURE OF LYSYL-TRNA SYNTHETASE FROM Cryptosporidium parvum COMPLEXED WITH L-LYSINE AND INHIBITOR DDD01887015
This is a non-PDB format compatible entry.
Summary for 9R32
| Entry DOI | 10.2210/pdb9r32/pdb |
| Descriptor | Lysine--tRNA ligase, 2-azanyl-6-[[(1~{S},3~{S})-1-oxidanyl-3-(trifluoromethyl)cyclohexyl]methyl]-4-(trifluoromethyl)-7~{H}-pyrrolo[3,4-d]pyrimidin-5-one, 1,2-ETHANEDIOL, ... (8 entities in total) |
| Functional Keywords | inhibitor, ligase |
| Biological source | Cryptosporidium parvum Iowa II |
| Total number of polymer chains | 4 |
| Total formula weight | 249680.12 |
| Authors | |
| Primary citation | Forte, B.,Bellany, F.,Campbell, P.S.,Chemi, G.,Dawson, A.,Anderson, M.,Aniweh, Y.,Burkhard, A.Y.,Aguiar, A.C.C.,Churchyard, A.,Cooper, C.A.,Dos Santos Ferreira, A.,Famodimu, M.T.,Fang, F.G.,Hu, X.,Huijs, T.,Baud, D.,Jansen, C.,Jimenez Diaz, M.B.,Bonnert, R.,Boyd, S.,Crespo-Fernandez, B.,Mitasev, B.,Montagna, S.,Mok, S.,Murugesan, D.,Narwal, S.K.,Norcross, N.R.,Okombo, J.,Park, H.,Peet, C.,Pereira, D.B.,Post, J.M.,Reader, J.,Riley, J.,Robinson, D.A.,Shinkyo, R.,Simeons, F.R.C.,Simpson, L.,Smith, A.,Smith, D.,Striepen, J.,Teles, C.B.G.,van der Laak, R.,Uhlemann, A.C.,Vantaux, A.,Wilson, C.,Witkowski, B.,Wood, G.,Yeo, T.,Zuccotto, F.,Angulo-Barturen, I.,Baum, J.,Bolscher, J.M.,Guido, R.V.C.,Birkholtz, L.M.,Delves, M.J.,Dembele, L.,Fidock, D.A.,Gamo, F.J.,Kyle, D.E.,Maher, S.P.,Popovici, J.,Walpole, C.,Gusovsky, F.,Willis, P.A.,Read, K.D.,Gilbert, I.H.,Baragana, B. Structure-Guided Optimization of Novel Inhibitors of Plasmodium Lysyl-tRNA Synthetase with Multistage Activity against Malaria Parasites. J.Med.Chem., 2026 Cited by PubMed Abstract: A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγ (SCID) mouse model. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor () with an extended half-life to reduce the dose regimen to a single-dose cure. Compound displayed a long half-life across preclinical species, favorable safety, and activity across species as well as against drug-resistant and sensitive strains and field isolates. Unfortunately, lacked oral bioavailability, which could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future KRS programs in delivering a clinical candidate with this novel mode of action. PubMed: 42227818DOI: 10.1021/acs.jmedchem.6c00823 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
Download full validation report
