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Structure. 2018 Jan 2;26(1):130-136.e2. doi: 10.1016/j.str.2017.11.021. Epub 2017 Dec 21.

Structure of the G119S Mutant Acetylcholinesterase of the Malaria Vector Anopheles gambiae Reveals Basis of Insecticide Resistance.

Author information

1
New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. Electronic address: jcheung@nysbc.org.
2
New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.
3
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.

Abstract

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.

KEYWORDS:

acetylcholinesterase; channel; difluoromethyl ketone; insecticide; malaria; resistance; selectivity

PMID:
29276037
PMCID:
PMC5752620
[Available on 2019-01-02]
DOI:
10.1016/j.str.2017.11.021
[Indexed for MEDLINE]

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