6A2L
Crystal structure of quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum DHFR-TS complexed with BT1, NADPH, and dUMP
Summary for 6A2L
| Entry DOI | 10.2210/pdb6a2l/pdb |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, 5-(3-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)-6-ethylpyrimidine-2,4-diamine, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total) |
| Functional Keywords | rossmann fold, dual-binding inhibitor, oxidoreductase |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 2 |
| Total formula weight | 146768.44 |
| Authors | Chitnumsub, P.,Jaruwat, A.,Tarnchampoo, B.,Yuthavong, Y. (deposition date: 2018-06-12, release date: 2019-04-24, Last modification date: 2023-11-22) |
| Primary citation | Tarnchompoo, B.,Chitnumsub, P.,Jaruwat, A.,Shaw, P.J.,Vanichtanankul, J.,Poen, S.,Rattanajak, R.,Wongsombat, C.,Tonsomboon, A.,Decharuangsilp, S.,Anukunwithaya, T.,Arwon, U.,Kamchonwongpaisan, S.,Yuthavong, Y. Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance. ACS Med Chem Lett, 9:1235-1240, 2018 Cited by PubMed Abstract: The S108N mutation of dihydrofolate reductase (DHFR) renders malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced. PubMed: 30613332DOI: 10.1021/acsmedchemlett.8b00389 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.38 Å) |
Structure validation
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