Journal
STRUCTURE
Volume 26, Issue 1, Pages 130-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2017.11.021
Keywords
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Funding
- New York Structural Biology Center (NYSBC)
- NIH [R01 AI082581]
- National Institute of General Medical Sciences from the NIH [P41 GM103403]
- NIH-ORIP HEI grant [S10 RR029205]
- DOE Office of Science [DE-AC02-06CH11357]
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR029205] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI082581] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103403] Funding Source: NIH RePORTER
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Malaria is a devastating disease in sub-Saharan Africa and is transmitted by the mosquito Anopheles gambiae. While indoor residual spraying of anticholinesterase insecticides has been useful in controlling the spread of malaria, widespread application of these compounds has led to the rise of an insecticide-resistant mosquito strain that harbors a G119S mutation in the nervous system target enzyme acetylcholinesterase. We demonstrate the atomic basis of insecticide resistance through structure determination of the G119S mutant acetylcholinesterase of An. gambiae in the ligand-free state and bound to a potent difluoromethyl ketone inhibitor. These structures reveal specific features within the active-site gorge distinct from human acetylcholinesterase, including an open channel at the base of the gorge, and provide a means for improving species selectivity in the rational design of improved insecticides for malaria vector control.
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