title: Crystal structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum at 2.25 A resolution reveals intriguing extra electron density in the active site.
abstract: 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.
authors.affiliation: Structural Genomics of Pathogenic Protozoa (SGPP), Department of Biochemistry, University of Washington, Seattle 98195, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Robien
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bosch
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Wesley C E
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Worthey
authors.forename: Peter
authors.initials: P
authors.lastname: Myler
authors.forename: Christopher
authors.initials: C
authors.lastname: Mehlin
authors.forename: Erica E
authors.initials: EE
authors.lastname: Boni
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Kalyuzhniy
authors.forename: Lori
authors.initials: L
authors.lastname: Anderson
authors.forename: Angela
authors.initials: A
authors.lastname: Lauricella
authors.forename: Stacy
authors.initials: S
authors.lastname: Gulde
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Luft
authors.forename: George
authors.initials: G
authors.lastname: DeTitta
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Caruthers
authors.forename: Keith O
authors.initials: KO
authors.lastname: Hodgson
authors.forename: Michael
authors.initials: M
authors.lastname: Soltis
authors.forename: Frank
authors.initials: F
authors.lastname: Zucker
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Merritt
authors.forename: Lori W
authors.initials: LW
authors.lastname: Schoenfeld
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000201:enzymology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: D021122:Protein Subunits; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D009243:NAD; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases