Download MendeleyHigh resolution structures of Plasmodium falciparum GST complexes provide novel insights into the dimer-tetramer transition and a novel ligand-binding site.
Perbandt, M., Eberle, R., Fischer-Riepe, L., Cang, H., Liebau, E., Betzel, C.(2015) J Struct Biol 191: 365-375
- PubMed: 26072058
- DOI: https://doi.org/10.1016/j.jsb.2015.06.008
- Primary Citation of Related Structures:
4ZXG - PubMed 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.
Organizational 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.
