Crystal structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum at 1.25 Å resolution reveals intriguing extra electron density in the active site

Mark A. Robien, Jürgen Bosch, Frederick S. Buckner, Wesley C E Van Voorhis, Elizabeth A. Worthey, Peter Myler, Christopher Mehlin, Erica E. Boni, Oleksandr Kalyuzhniy, Lori Anderson, Angela Lauricella, Stacy Gulde, Joseph R. Luft, George DeTitta, Jonathan M. Caruthers, Keith O. Hodgson, Michael Soltis, Frank Zucker, Christophe L M J Verlinde, Ethan A. MerrittLori W. Schoenfeld, Wim G J Hol

Research output: Contribution to journalArticlepeer-review

Abstract

The crystal structure of D-glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH) from the major malaria parasite Plasmodium falciparum is solved at 2.25 Å 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.

Original languageEnglish (US)
Pages (from-to)570-577
Number of pages8
JournalProteins
Volume62
Issue number3
DOIs
StatePublished - Feb 15 2006
Externally publishedYes

Keywords

  • Drug design
  • GAPDH
  • Malaria
  • NAD
  • Structural genomics

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

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