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2 Department of Pharmacology/Crystallography Centre, University of Western Australia, Crawley 6009, Australia
3 Institute of Molecular Biology and Genetics, Mahidol University, Salaya Campus, Nakorn Pathom 73170, Thailand
Reprint requests to: Dr. Matthew Wilce, Department of Pharmacology, University of Western Australia, 35 Stirling Highway, Crawley 6009, Australia; e-mail: mwilce{at}receptor.pharm.uwa.edu.au; fax: 61-8-9346-3469.
Glutathione S-transferases (GSTs) are dimeric proteins that play an important role in cellular detoxification. Four GSTs from the mosquito Anopheles dirus species B (Ad), an important malaria vector in South East Asia, are produced by alternate splicing of a single transcription product and were previously shown to have detoxifying activity towards pesticides such as DDT. We have determined the crystal structures for two of these alternatively spliced proteins, AdGST1–3 (complexed with glutathione) and AdGST1–4 (apo form), at 1.75 and 2.45 Å resolution, respectively. These GST isozymes show differences from the related GST from the Australian sheep blowfly Lucilia cuprina; in particular, the presence of a C-terminal helix forming part of the active site. This helix causes the active site of the Anopheles GSTs to be enclosed. The glutathione-binding helix 
2 and flanking residues are disordered in the AdGST1–4 (apo) structure, yet ordered in the AdGST1–3 (GSH-bound) structure, suggesting that insect GSTs operate with an induced fit mechanism similar to that found in the plant phi- and human pi-class GSTs. Despite the high overall sequence identities, the active site residues of AdGST1–4 and AdGST1–3 have different conformations.
Keywords: Glutathione S-transferase; induced fit; mosquito; Anopheles dirus species B; pesticide resistance
Abbreviations: GST, glutathione S-transferase • GSH, glutathione • Ad, Anopheles dirus species B • Lc, Lucilia cuprina
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