title: High resolution structures of Plasmodium falciparum GST complexes provide novel insights into the dimer-tetramer transition and a novel ligand-binding site.
abstract: Protection from oxidative stress and efficient redox regulation are essential for malarial parasites which have to grow and multiply rapidly in pro-oxidant rich environments. Therefore, redox active proteins currently belong to the most attractive antimalarial drug targets. The glutathione S-transferase from Plasmodium falciparum (PfGST) is a redox active protein displaying a peculiar dimer-tetramer transition that causes full enzyme-inactivation. This distinct structural feature is absent in mammalian GST isoenzyme counterparts. A flexible loop between residues 113-119 has been reported to be necessary for this tetramerization process. However, here we present structural data of a modified PfGST lacking loop 113-119 at 1.9 Å resolution. Our results clearly show that this loop is not essential for the formation of stable tetramers. Moreover we present for the first time the structures of both, the inactive and tetrameric state at 1.7 Å and the active dimeric state in complex with reduced glutathione at 2.4 Å resolution. Surprisingly, the structure of the inactive tetrameric state reveals a novel non-substrate binding-site occupied by a 2-(N-morpholino) ethane sulfonic acid (MES) molecule in each monomer. Although it is known that the PfGST has the ability to bind lipophilic anionic ligands, the location of the PfGST ligand-binding site remained unclear up to now.
authors.affiliation: Institute of Biochemistry and Molecular Biology, University of Hamburg, Laboratory of Structural Biology of Infection and Inflammation, c/o DESY, Notkestr. 85, Build. 22a, D-22603 Hamburg, Germany; Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf (UKE), D-20246 Hamburg, Germany; The Hamburg Centre for Ultrafast Imaging, Luruper Chaussee 149, D-22761 Hamburg, Germany. Electronic address: markus.perbandt@uni-hamburg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Perbandt
authors.affiliation: Institute of Biochemistry and Molecular Biology, University of Hamburg, Laboratory of Structural Biology of Infection and Inflammation, c/o DESY, Notkestr. 85, Build. 22a, D-22603 Hamburg, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Eberle
authors.affiliation: Department of Molecular Physiology, University of Münster, Schlossplatz 8, D-48143 Münster, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Fischer-Riepe
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Huaixing
authors.initials: H
authors.lastname: Cang
authors.affiliation: Department of Molecular Physiology, University of Münster, Schlossplatz 8, D-48143 Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Liebau
authors.affiliation: Institute of Biochemistry and Molecular Biology, University of Hamburg, Laboratory of Structural Biology of Infection and Inflammation, c/o DESY, Notkestr. 85, Build. 22a, D-22603 Hamburg, Germany; The Hamburg Centre for Ultrafast Imaging, Luruper Chaussee 149, D-22761 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Betzel
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D019281:Dimerization; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D008024:Ligands; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000378:metabolism*
chemical_list: D008024:Ligands; D005982:Glutathione Transferase; D005978:Glutathione
keywords: GST; Glutathione S-transferase; Ligandin; Malaria; Non-substrate binding site; Tetramerization