Structure of an insect δ-class glutathione S-transferase from a DDT-resistant strain of the malaria vector Anopheles gambiae

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 Å resolution. The structure adopts a classical GST fold and is similar to those of other insect δ‐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.