title: Structure of an insect delta-class glutathione S-transferase from a DDT-resistant strain of the malaria vector Anopheles gambiae.
abstract: Glutathione S-transferases (GSTs) are a major family of detoxification enzymes which possess a wide range of substrate specificities. Most organisms possess many GSTs belonging to multiple classes. Interest in GSTs in insects is focused on their role in insecticide resistance; many resistant insects have elevated levels of GST activity. In the malaria vector Anopheles gambiae, elevated GST levels are associated with resistance to the organochlorine insecticide DDT [1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane]. This mosquito is the source of an insect GST, agGSTd1-6, which metabolizes DDT and is inhibited by a number of pyrethroid insecticides. The crystal structure of agGSTd1-6 in complex with its inhibitor S-hexyl glutathione has been determined and refined at 2.0 A resolution. The structure adopts a classical GST fold and is similar to those of other insect delta-class GSTs, implying a common conjugation mechanism. A structure-based model for the binding of DDT to agGSTd1-6 reveals two subpockets in the hydrophobic binding site (H-site), each accommodating one planar p-chlorophenyl ring.
authors.affiliation: Laboratory for Structural Biology, Department of Chemistry, Graduate Programs of Biotechnology, Chemistry and Materials Science, University of Alabama in Huntsville, Huntsville, AL 35899, USA. chenlq@email.uah.edu
authors.forename: Liqing
authors.initials: L
authors.lastname: Chen
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Hall
authors.forename: Xiaoyin E
authors.initials: XE
authors.lastname: Zhou
authors.forename: Hilary
authors.initials: H
authors.lastname: Ranson
authors.forename: Janet
authors.initials: J
authors.lastname: Hemingway
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Meehan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000852:Anopheles / Q000201:enzymology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003634:DDT / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007303:Insect Vectors / Q000201:enzymology*; D007305:Insecticide Resistance; D008288:Malaria / Q000635:transmission; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
chemical_list: D004791:Enzyme Inhibitors; D003634:DDT; D005982:Glutathione Transferase; D005978:Glutathione; C033550:hexylglutathione