5YG2
Plasmodium vivax SHMT bound with PLP-glycine and GS705
Summary for 5YG2
| Entry DOI | 10.2210/pdb5yg2/pdb |
| Descriptor | Serine hydroxymethyltransferase, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], 3-[1-[3-[(4~{S})-6-azanyl-5-cyano-3-methyl-4-propan-2-yl-2~{H}-pyrano[2,3-c]pyrazol-4-yl]-5-fluoranyl-phenyl]piperidin-4-yl]propanoic acid, ... (5 entities in total) |
| Functional Keywords | alpha and beta protein, transferase, methyltransferase activity, inhibitor, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Plasmodium vivax |
| Total number of polymer chains | 3 |
| Total formula weight | 150139.62 |
| Authors | Chitnumsub, P.,Jaruwat, A.,Leartsakulpanich, U.,Schwertz, G.,Diederich, F. (deposition date: 2017-09-22, release date: 2018-06-06, Last modification date: 2023-11-22) |
| Primary citation | Schwertz, G.,Witschel, M.C.,Rottmann, M.,Leartsakulpanich, U.,Chitnumsub, P.,Jaruwat, A.,Amornwatcharapong, W.,Ittarat, W.,Schafer, A.,Aponte, R.A.,Trapp, N.,Chaiyen, P.,Diederich, F. Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold ChemMedChem, 13:931-943, 2018 Cited by PubMed Abstract: With the discovery that serine hydroxymethyltransferase (SHMT) is a druggable target for antimalarials, the aim of this study was to design novel inhibitors of this key enzyme in the folate biosynthesis cycle. Herein, 19 novel spirocyclic ligands based on either 2-indolinone or dihydroindene scaffolds and featuring a pyrazolopyran core are reported. Strong target affinities for Plasmodium falciparum (Pf) SHMT (14-76 nm) and cellular potencies in the low nanomolar range (165-334 nm) were measured together with interesting selectivity against human cytosolic SHMT1 (hSHMT1). Four co-crystal structures with Plasmodium vivax (Pv) SHMT solved at 2.2-2.4 Å resolution revealed the key role of the vinylogous cyanamide for anchoring ligands within the active site. The spirocyclic motif in the molecules enforces the pyrazolopyran core to adopt a substantially more curved conformation than that of previous non-spirocyclic analogues. Finally, solvation of the spirocyclic lactam ring of the receptor-bound ligands is discussed. PubMed: 29655285DOI: 10.1002/cmdc.201800053 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
Download full validation report
