5XMV
Plasmodium vivax SHMT bound with PLP-glycine and GS362
Summary for 5XMV
| Entry DOI | 10.2210/pdb5xmv/pdb |
| Descriptor | Serine hydroxymethyltransferase, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], (4~{S})-6-azanyl-4-[3-(2-chlorophenyl)-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2~{H}-pyrano[2,3-c]pyrazole-5- carbonitrile, ... (5 entities in total) |
| Functional Keywords | alpha and beta protein, transferase, methyltransferase activity, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Plasmodium vivax |
| Total number of polymer chains | 3 |
| Total formula weight | 150155.68 |
| Authors | Chitnumsub, P.,Jaruwat, A.,Leartsakulpanich, U.,Schwertz, G.,Diederich, F. (deposition date: 2017-05-16, release date: 2017-11-29, Last modification date: 2023-11-22) |
| Primary citation | Schwertz, G.,Frei, M.S.,Witschel, M.C.,Rottmann, M.,Leartsakulpanich, U.,Chitnumsub, P.,Jaruwat, A.,Ittarat, W.,Schafer, A.,Aponte, R.A.,Trapp, N.,Mark, K.,Chaiyen, P.,Diederich, F. Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs Chemistry, 23:14345-14357, 2017 Cited by PubMed Abstract: Malaria remains a major threat to mankind due to the perpetual emergence of resistance against marketed drugs. Twenty-one pyrazolopyran-based inhibitors bearing terminal biphenyl, aryl sulfonamide, or aryl sulfone motifs were synthesized and tested towards serine hydroxymethyltransferase (SHMT), a key enzyme of the folate cycle. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target, as well as PfNF54 strains in cell-based assays in the low nanomolar range (18-56 nm). Seven co-crystal structures with P. vivax (Pv) SHMT were solved at 2.2-2.6 Å resolution. We observed an unprecedented influence of the torsion angle of ortho-substituted biphenyl moieties on cell-based efficacy. The peculiar lipophilic character of the sulfonyl moiety was highlighted in the complexes with aryl sulfonamide analogues, which bind in their preferred staggered orientation. The results are discussed within the context of conformational preferences in the ligands. PubMed: 28967982DOI: 10.1002/chem.201703244 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.16 Å) |
Structure validation
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