title: Homology modelling of Drosophila cytochrome P450 enzymes associated with insecticide resistance.
abstract: BACKGROUND
  Overexpression of the cytochrome P450 gene Cyp6g1 confers resistance against DDT and a broad range of other insecticides in Drosophila melanogaster Meig. In the absence of crystal structures of CYP6G1 or complexes with its substrates, structural studies rely on homology modelling and ligand docking to understand P450-substrate interactions.
  
  
  RESULTS
  Homology models are presented for CYP6G1, a P450 associated with resistance to DDT and neonicotinoids, and two other enzymes associated with insecticide resistance in D. melanogaster, CYP12D1 and CYP6A2. The models are based on a template of the X-ray structure of the phylogenetically related human CYP3A4, which is known for its broad substrate specificity. The model of CYP6G1 has a much smaller active site cavity than the template. The cavity is also 'V'-shaped and is lined with hydrophobic residues, showing high shape and chemical complementarity with the molecular characteristics of DDT. Comparison of the DDT-CYP6G1 complex and a non-resistant CYP6A2 homology model implies that tight-fit recognition of this insecticide is important in CYP6G1. The active site can accommodate differently shaped substrates ranging from imidacloprid to malathion but not the pyrethroids permethrin and cyfluthrin.
  
  
  CONCLUSIONS
  The CYP6G1, CYP12D1 and CYP6A2 homology models can provide a structural insight into insecticide resistance in flies overexpressing P450 enzymes with broad substrate specificities.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, UK.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jones
authors.forename: Saskia E
authors.initials: SE
authors.lastname: Bakker
authors.forename: Deborah
authors.initials: D
authors.lastname: Stone
authors.forename: Sally N
authors.initials: SN
authors.lastname: Shuttleworth
authors.forename: Sam
authors.initials: S
authors.lastname: Boundy
authors.forename: Caroline
authors.initials: C
authors.lastname: McCart
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Daborn
authors.forename: Richard H
authors.initials: RH
authors.lastname: ffrench-Constant
authors.forename: Jean M H
authors.initials: JM
authors.lastname: van den Elsen
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072472:Cytochrome P450 Family 6; D003634:DDT / Q000378:metabolism / Q000494:pharmacology; D004330:Drosophila / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007305:Insecticide Resistance; D007306:Insecticides / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D029721:Drosophila Proteins; D007306:Insecticides; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; C554957:cytochrome P-450 12D1, Drosophila; C446928:Cyp6g1 protein, Drosophila; C109499:Cyp6a2 protein, Drosophila; D000072472:Cytochrome P450 Family 6