5GVM
Plasmodium vivax SHMT bound with PLP-glycine and GS557
Summary for 5GVM
| Entry DOI | 10.2210/pdb5gvm/pdb |
| Related | 5GMK 5GML 5GMN 5GMP |
| Descriptor | Serine hydroxymethyltransferase, putative, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], 2-[3-[3-[(4~{S})-6-azanyl-5-cyano-3-methyl-4-propan-2-yl-2~{H}-pyrano[2,3-c]pyrazol-4-yl]-5-(trifluoromethyl)phenyl]phenyl]ethanoic acid, ... (5 entities in total) |
| Functional Keywords | alpha and beta protein, methyltransferase activity, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Plasmodium vivax (strain Salvador I) |
| Total number of polymer chains | 3 |
| Total formula weight | 150226.46 |
| Authors | Chitnumsub, P.,Jaruwat, A.,Leartsakulpanich, U.,Schwertz, G. (deposition date: 2016-09-06, release date: 2017-07-12, Last modification date: 2023-11-08) |
| Primary citation | Schwertz, G.,Witschel, M.C.,Rottmann, M.,Bonnert, R.,Leartsakulpanich, U.,Chitnumsub, P.,Jaruwat, A.,Ittarat, W.,Schafer, A.,Aponte, R.A.,Charman, S.A.,White, K.L.,Kundu, A.,Sadhukhan, S.,Lloyd, M.,Freiberg, G.M.,Srikumaran, M.,Siggel, M.,Zwyssig, A.,Chaiyen, P.,Diederich, F. Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures J. Med. Chem., 60:4840-4860, 2017 Cited by PubMed Abstract: Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 Å resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel. PubMed: 28537728DOI: 10.1021/acs.jmedchem.7b00008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.24 Å) |
Structure validation
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