2BLB

X-ray crystal structure of Plasmodium vivax dihydrofolate reductase in complex with pyrimethamine and its derivative

Summary for 2BLB

• Entry DOI: 10.2210/pdb2blb/pdb
• Related: 2BL9 2BLA 2BLC
• Descriptor: DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-ETHYL-5-PHENYLPYRIMIDINE-2,4-DIAMINE, ... (5 entities in total)
• Functional Keywords: dihydrofolate reductase, plamodium vivax, pyrimethamine, malaria, drug resistance, oxidoreductase
• Biological source: PLASMODIUM VIVAX
• Total number of polymer chains: 1
• Total formula weight: 28265.92

Authors

Kongsaeree, P.,Khongsuk, P.,Leartsakulpanich, U.,Chitnumsub, P.,Tarnchompoo, B.,Walkinshaw, M.D.,Yuthavong, Y. (deposition date: 2005-03-03, release date: 2005-09-07, Last modification date: 2024-05-08)

Primary citation

Kongsaeree, P.,Khongsuk, P.,Leartsakulpanich, U.,Chitnumsub, P.,Tarnchompoo, B.,Walkinshaw, M.D.,Yuthavong, Y.
Crystal Structure of Dihydrofolate Reductase from Plasmodium Vivax: Pyrimethamine Displacement Linked with Mutation-Induced Resistance.
Proc.Natl.Acad.Sci.USA, 102:13046-, 2005

PubMed Abstract: Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 --> Arg + Ser-117 --> Asn) strain as complexes with NADPH and Pyr or its analog lacking p-Cl (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes.

PubMed: 16135570
DOI: 10.1073/PNAS.0501747102

Experimental method

X-RAY DIFFRACTION (3 Å)