The atomic basis of insecticide-resistance in malaria mosquitoes revealed by X-ray crystallography2018-01-30T17:43:44+00:00

Scientists in the Special Projects Group at NYSBC have determined X-ray crystal structures of the G119S mutant acetylcholinesterase (G119S AgAChE) of the malaria mosquito Anopheles gambiae.  Malaria is a devastating disease in many developing nations, and successful efforts to reduce malaria transmission by use of anti-cholinesterase insecticides to control populations of the mosquito are at risk due to emergence of a recurring G119S mutation in the enzyme that specifically confers insecticide-resistance.  This mutation presents a steric block against binding of mosquitocides to the catalytic site at the base of the active site gorge.  Although potent inhibitors have been developed against the mutant protein, they also inhibit human acetylcholinesterase (hAChE) and thus they are not suitable for use as insecticides due to human toxicity concerns.  Structures of G119S AgAChE solved to 2.3 Å reveal unique features, including an open back channel at the base of the active site gorge, not seen in hAChE.  These high resolution structures provide the necessary foundation for structure-guided design of improved resistance-breaking and species-selective insecticides to control vector populations in the effort to reduce malaria transmission.

 

A cross-section through the active side gorge of structures of G119S AgAChE and hAChE are shown side-by-side, drawn as electrostatic molecular surfaces with select residues drawn as sticks.  Protein full length numbering is used, and S280 is the residue that confers insecticide-resistance.