Robien Mark A, Bosch Jürgen, Buckner Frederick S, Van Voorhis Wesley C E, Worthey Elizabeth A, Myler Peter, Mehlin Christopher, Boni Erica E, Kalyuzhniy Oleksandr, Anderson Lori, Lauricella Angela, Gulde Stacy, Luft Joseph R, DeTitta George, Caruthers Jonathan M, Hodgson Keith O, Soltis Michael, Zucker Frank, Verlinde Christophe L M J, Merritt Ethan A, Schoenfeld Lori W, Hol Wim G J
Structural Genomics of Pathogenic Protozoa (SGPP), Department of Biochemistry, University of Washington, Seattle 98195, USA.
Proteins. 2006 Mar 15;62(3):570-7. doi: 10.1002/prot.20801.
The crystal structure of D-glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH) from the major malaria parasite Plasmodium falciparum is solved at 2.25 A resolution. The structure of PfGAPDH is of interest due to the dependence of the malaria parasite in infected human erythrocytes on the glycolytic pathway for its energy generation. Recent evidence suggests that PfGAPDH may also be required for other critical activities such as apical complex formation. The cofactor NAD(+) is bound to all four subunits of the tetrameric enzyme displaying excellent electron densities. In addition, in all four subunits a completely unexpected large island of extra electron density in the active site is observed, approaching closely the nicotinamide ribose of the NAD(+). This density is most likely the protease inhibitor AEBSF, found in maps from two different crystals. This putative AEBSF molecule is positioned in a crucial location and hence our structure, with expected and unexpected ligands bound, can be of assistance in lead development and design of novel antimalarials.
