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Biologische Systeme und Medizin Poster: Mi., 14:00–16:30 M-P204
Structure of the prostaglandin D synthase from the parasitic nematode
Onchocerca volvulus
Markus Perbandt 1 , Jana Höppner 2 , Jörg Degen 3 , Christian Betzel 1 , Eva
Liebau 4
1 Department of Biochemistry and Molecularbiology, University of Hamburg, Martin
Luther King Platz 6, 20146 Hamburg, Germany – 2 Department of Biochemistry, Bernhard
Nocht Institute for Tropical Medicine – 3 Center of Bioinformatics, University of
Hamburg, Bundesstraße 43, 20146 Hamburg, Germany – 4 Institute of Zoo Physiology,
Department of Molecular Physiology, Westfälische Wilhelms-University of Münster
Onchocerciasis or river-blindness is a debilitating parasitic disease caused by the filarial
worm, Onchocerca volvulus. Chemotherapeutic approaches to control parasite
transmission and to treat onchocerciasis rely on drugs that only kill microfilariae and
infectious larvae but not the adult parasites. So far this necessitates the continuous
use of these microfilaricides until the adult worms die. Therefore, the development
of drugs that also effectively kill the adult worms would greatly support the control
and treatment of O. volvulus infections [1]. Furthermore, the potential development
of drug-resistant strains of the nematode also demands the identification of alternative
drug candidates to control the disease [2].
The long-term survival of the parasites in the host is remarkable and has initiated a
search for parasite-derived molecules that are involved in the modulation of the host
immune system. The glutathione-dependent prostaglandin D synthase (Ov-GST1)
from O. volvulus is strongly in involved in this and belongs to the sigma class of
the glutathione S-transferase (GST) family. It is located directly at the parasite-host
interface. The data were collected at DESY/HASYLAB in Hamburg using synchrotron
radiation. We analysed the three-dimensional structure of the enzyme complexed with
glutathione at 2.0 ˚A. The molecular architecture of the substrate binding site reveals
significant differences to the vertebrate orthologs from human and rat.
The putative substrate binding mode and its catalytic mechanism for the specific isomerization
from PGH2 to PGD2 is proposed based on the structural insights. Knowing
the three-dimensional shape and chemical nature of the enzyme binding pocket will aid
in the discovery and design of novel anti-filarial compounds.
[1] D.H. Molyneux et al., Trends Parasitol 19 (2003) 516-522.
[2] N. Sangster, Parasitology 113 Suppl (1996) 201-216.