Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase: structure, catalytic mechanism and targeted inhibitor design.
(1998) FEBS Letters — Vol. 424, n° 3, p. 131-135 (1998)
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- Abstract
- The 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 A includes the bound cofactor NAD+ and 90 water molecules per monomer and resulted in an Rfactor of 20.1%, Rfree = 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 Arg249 which as a consequence forms a salt bridge to Asp210 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 Asp210 is a leucine in the mammalian enzymes.
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Souza, D. H., Garratt, R. C., Araújo, A. P., Guimarães, B. G., Jesus, W. D., Michels, P., Hannaert, V., & Oliva, G. (1998). Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase: structure, catalytic mechanism and targeted inhibitor design. FEBS Letters, 424(3), 131-135. https://doi.org/10.1016/S0014-5793(98)00154-9 (Original work published 1998)