1m7p
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Plasmodium Falciparum Triosephosphate isomerase (PfTIM) compled to substrate analog glycerol-3-phosphate (G3P).
OverviewOverview
The glycolytic enzymes of Plasmodium falciparum (Pf) are attractive drug, targets as the parasites lack a functional tricarboxylic cycle and hence, depend heavily on glycolysis for their energy requirements. Structural, comparisons between Pf triosephosphate isomerase (PfTIM) and its human, homologue have highlighted the important differences between the host and, parasite enzymes [Velanker et al. (1997), Structure, 5, 751-761]., Structures of various PfTIM-ligand complexes have been determined in order, to gain further insight into the mode of inhibitor binding to the parasite, enzyme. Structures of two PfTIM-substrate analogue complexes, those of, 3-phosphoglycerate (3PG) and glycerol-3-phosphate (G3P), have been, determined and refined at 2.4 A resolution. Both complexes crystallized in, the monoclinic space group P2(1), with a molecular dimer in the asymmetric, unit. The novel aspect of these structures is the adoption of the, 'loop-open' conformation, with the catalytic loop (loop 6, residues, 166-176) positioned away from the active site; this loop is known to move, by about 7 A towards the active site upon inhibitor binding in other TIMs., The loop-open form in the PfTIM complexes appears to be a consequence of, the S96F mutation, which is specific to the enzymes from malarial, parasites. Structural comparison with the corresponding complexes of, Trypanosoma brucei TIM (TrypTIM) shows that extensive steric clashes may, be anticipated between Phe96 and Ile172 in the 'closed' conformation of, the catalytic loop, preventing loop closure in PfTIM. Ser73 in PfTIM (Ala, in all other known TIMs) appears to provide an anchoring water-mediated, hydrogen bond to the ligand, compensating for the loss of a stabilizing, hydrogen bond from Gly171 NH in the closed-loop liganded TIM structures.
About this StructureAbout this Structure
1M7P is a Single protein structure of sequence from Plasmodium falciparum with G3H as ligand. Active as Triose-phosphate isomerase, with EC number 5.3.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Structures of Plasmodium falciparum triosephosphate isomerase complexed to substrate analogues: observation of the catalytic loop in the open conformation in the ligand-bound state., Parthasarathy S, Balaram H, Balaram P, Murthy MR, Acta Crystallogr D Biol Crystallogr. 2002 Dec;58(Pt 12):1992-2000. Epub, 2002 Nov 23. PMID:12454456
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