1M7P

Plasmodium Falciparum Triosephosphate isomerase (PfTIM) compled to substrate analog glycerol-3-phosphate (G3P).

Summary for 1M7P

• Entry DOI: 10.2210/pdb1m7p/pdb
• Related: 1LYX 1LZO 1M7O 1YDV
• Descriptor: Triosephosphate Isomerase, GLYCERALDEHYDE-3-PHOSPHATE (3 entities in total)
• Functional Keywords: tim barrles; beta-alpha barrels; enzyme-inhibitor complex, isomerase
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum)
• Total number of polymer chains: 2
• Total formula weight: 56335.59

Authors

Parthasarathy, S.,Balaram, H.,Balaram, P.,Murthy, M.R.N. (deposition date: 2002-07-22, release date: 2002-11-29, Last modification date: 2024-02-14)

Primary citation

Parthasarathy, S.,Balaram, H.,Balaram, P.,Murthy, M.R.
Structures of Plasmodium falciparum triosephosphate isomerase complexed to substrate analogues: observation of the catalytic loop in the open conformation in the ligand-bound state.
Acta Crystallogr.,Sect.D, 58:1992-2000, 2002

PubMed Abstract: 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.

PubMed: 12454456
DOI: 10.1107/S0907444902015433

Experimental method

X-RAY DIFFRACTION (2.4 Å)