Structure of the Extracellular Glutathione S -Transferase OvGST1 from the Human Pathogenic Parasite Onchocerca volvulus Markus Perbandt 1,2 ⁎, Jana Höppner 3 , Cora Burmeister 3 , Kai Lüersen 3 , Christian Betzel 2 and Eva Liebau 3 1 Institute of Biochemistry, Center for Structural and Cell Biology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany 2 Institute of Biochemistry and Molecular Biology, University of Hamburg, Martin Luther King Platz 6, 22603 Hamburg, Germany 3 Institute for Animal Physiology, University of Muenster, Hindenburgplatz 55, 48143 Muenster, Germany Received 8 November 2007; received in revised form 9 January 2008; accepted 9 January 2008 Available online 16 January 2008 Onchocerciasis or river blindness, caused by the filarial worm Onchocerca volvulus, is the world’s second leading infectious cause of blindness. In order to chronically infect the host, O. volvulus has evolved molecular strategies that influence and direct immune responses away from the modes most damaging to it. The O. volvulus GST1 (OvGST1) is a unique glutathione S-transferase (GST) in that it is a glycoprotein and possesses a signal peptide that is cleaved off in the process of maturation. The mature protein starts with a 25-amino-acid extension not present in other GSTs. In all life stages of the filarial worm, it is located directly at the parasite–host interface. Here, the OvGST1 functions as a highly specific glutathione-dependent prosta- glandin D synthase (PGDS). The enzyme therefore has the potential to participate in the modulation of immune responses by contributing to the production of parasite-derived prostanoids and restraining the host’s effector responses, making it a tempting target for chemotherapy and vaccine development. Here, we report the crystal structure of the OvGST1 bound to its cofactor glutathione at 2.0 Å resolution. The structure reveals an overall structural homology to the haematopoietic PGDS from vertebrates but, surprisingly, also a large conformational change in the prostaglandin binding pocket. The observed differences reveal a different vicinity of the prostaglandin H 2 binding pocket that demands another prostaglandin H 2 binding mode to that proposed for the vertebrate PGDS. Finally, a putative substrate binding mode for prostaglandin H 2 is postulated based on the observed structural insights. © 2008 Elsevier Ltd. All rights reserved. Edited by R. Huber Keywords: glutathione S-transferase; river blindness; prostglandin synthase; Onchocerca volvulus; onchocerciasis Introduction The filarial parasite Onchocerca volvulus is the causative agent of human onchocerciasis or river blindness, a disease characterized by chronic skin and eye lesions. It is the world’s second leading infectious cause of blindness. The World Health Organization estimates that more than 18 million people are infected, 500,000 are visually impaired and about 250,000 are blind. 1 However, it is felt that these figures underestimate the true magnitude of the problem. 2 Although not generally considered fatal, onchocerciasis causes chronic suffering and severe disability, significantly impeding socio-eco- nomic development in affected communities. Che- motherapeutic approaches to control parasite transmission and to treat onchocerciasis rely on ivermectin, an effective and safe microfilaricide. Mass administration once or twice a year reduces morbidity and disability and lowers transmission. 3 Since ivermectin kills only microfilariae, continuous use is necessary until the adult worm dies. The *Corresponding author. Institute of Biochemistry, Center for Structural and Cell Biology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. E-mail address: perbandt@biochem.uni-luebeck.de. Abbreviations used: GST, glutathione S-transferase; PGDS, prostaglandin D synthase; OvGST, O. volvolus GST; PGH 2 , prostaglandin H 2 ; GSH, glutathione. doi:10.1016/j.jmb.2008.01.029 J. Mol. Biol. (2008) 377, 501–511 Available online at www.sciencedirect.com 0022-2836/$ - see front matter © 2008 Elsevier Ltd. All rights reserved.