Trypanosoma cruzi glycosomal glyceraldehyde‐3‐phosphate dehydrogenase: structure, catalytic mechanism and targeted inhibitor design
1998; Wiley; Volume: 424; Issue: 3 Linguagem: Inglês
10.1016/s0014-5793(98)00154-9
ISSN1873-3468
AutoresDulce Helena Ferreira de Souza, Richard Charles Garratt, Ana Paula Ulian de Araújo, B.G. Guimarães, W D P Jesus, Paul A.M. Michels, V. Hannaert, Glaucius Oliva,
Tópico(s)RNA and protein synthesis mechanisms
ResumoThe structure of the enzyme glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) from glycosomes of the parasite Trypanosoma cruzi , causative agent of Chagas' disease, is reported. The final model at 2.8 Å includes the bound cofactor NAD + and 90 water molecules per monomer and resulted in an R factor of 20.1%, R free =22.3%, with good geometry indicators. The structure has no ions bound at the active site resulting in a large change in the side chain conformation of Arg 249 which as a consequence forms a salt bridge to Asp 210 in the present structure. We propose that this conformational change could be important for the reaction mechanism and possibly a common feature of many GAPDH structures. Comparison with the human enzyme indicates that interfering with this salt bridge could be a new approach to specific inhibitor design, as the equivalent to Asp 210 is a leucine in the mammalian enzymes.
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