Crystal structure of acetylcholinesterase catalytic subunits of the malaria vector <i>Anopheles gambiae</i>

Han, Qian; Wong, Dawn M.; Robinson, Howard; Ding, Huanjun; Lam, Polo C.‐H.; Totrov, Maxim; Carlier, Paul R.; Li, Jianyong

doi:10.1111/1744-7917.12450

Cited by 23 publications

(25 citation statements)

References 15 publications

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“…The sequence similarity of AgAChE and DmAChE is relatively low (41.1% identity) since they are coded by non-homologous genes, ace-1 and ace-2, respectively [9]. Their overall structures are, nevertheless, very similar (1.9 Å rmsd) [8]. The structure of AgAChE notably confirmed the existence of an open channel at the base of the active-site gorge [9], as previously identified in DmAChE [6].…”

Section: Introductionsupporting

confidence: 71%

“…These structures provided the first rational basis for explaining differences in specificity and activity between DmAChE and mammalian AChEs. Recently, crystal structures of another insect AChE have been published, that of the wild type Anopheles gambiae AChE (AgAChE) [8] and of an insecticide-resistant mutant of the same enzyme [9]. The sequence similarity of AgAChE and DmAChE is relatively low (41.1% identity) since they are coded by non-homologous genes, ace-1 and ace-2, respectively [9].…”

Section: Introductionmentioning

confidence: 99%

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A Second Look at the Crystal Structures of Drosophila melanogaster Acetylcholinesterase in Complex with Tacrine Derivatives Provides Insights Concerning Catalytic Intermediates and the Design of Specific Insecticides

Nachon¹,

Rosenberry

Silman

et al. 2020

Molecules

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Over recent decades, crystallographic software for data processing and structure refinement has improved dramatically, resulting in more accurate and detailed crystal structures. It is, therefore, sometimes valuable to have a second look at “old” diffraction data, especially when earlier interpretation of the electron density maps was rather difficult. Here, we present updated crystal structures of Drosophila melanogaster acetylcholinesterase (DmAChE) originally published in [Harel et al., Prot Sci (2000) 9:1063-1072], which reveal features previously unnoticed. Thus, previously unmodeled density in the native active site can be interpreted as stable acetylation of the catalytic serine. Similarly, a strong density in the DmAChE/ZA complex originally attributed to a sulfate ion is better interpreted as a small molecule that is covalently bound. This small molecule can be modeled as either a propionate or a glycinate. The complex is reminiscent of the carboxylate butyrylcholinesterase complexes observed in crystal structures of human butyrylcholinesterases from various sources, and demonstrates the remarkable ability of cholinesterases to stabilize covalent complexes with carboxylates. A very strong peak of density (10 σ) at covalent distance from the Cβ of the catalytic serine is present in the DmAChE/ZAI complex. This can be undoubtedly attributed to an iodine atom, suggesting an unanticipated iodo/hydroxyl exchange between Ser238 and the inhibitor, possibly driven by the intense X-ray irradiation. Finally, the binding of tacrine-derived inhibitors, such as ZA (1DX4) or the iodinated analog, ZAI (1QON) results in the appearance of an open channel that connects the base of the active-site gorge to the solvent. This channel, which arises due to the absence of the conserved tyrosine present in vertebrate cholinesterases, could be exploited to design inhibitors specific to insect cholinesterases. The present study demonstrates that updated processing of older diffraction images, and the re-refinement of older diffraction data, can produce valuable information that could not be detected in the original analysis, and strongly supports the preservation of the diffraction images in public data banks.

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Section: Introductionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

A Second Look at the Crystal Structures of Drosophila melanogaster Acetylcholinesterase in Complex with Tacrine Derivatives Provides Insights Concerning Catalytic Intermediates and the Design of Specific Insecticides

Nachon¹,

Rosenberry

Silman

et al. 2020

Molecules

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“…To compare the interaction of DEP with human AChE (hAChE) and An. gambiae AChE (AgAChE), DEP-bound hAChE (PDB ID: 5hf5) [43] was aligned to AgAChE (PDB ID: 5x61) [44] using PyMOL [45] (Fig. 3).…”

Section: Metabolic Proteins As Insecticide Targetsmentioning

confidence: 99%

“…These two studies suggest that Anopheles AChE can be selectively inhibited by more specific insecticides. Further studies towards identifying these selective inhibitors that could serve as novel insecticides are possible since the crystal structure of the catalytic domain of AgAChE is available [44]. Still, a new insecticide target should ideally be a protein that is important for the survival of target species and unique to them (i.e.…”

Section: Metabolic Proteins As Insecticide Targetsmentioning

confidence: 99%

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

et al. 2020

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The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an effective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identification of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmission exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specificity can yield insecticides with no significant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will significantly help to curb malaria transmission.

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“…No crystal structures of Anopheles arabienesis AChE from mosquito are deposited in the Protein Data Bank (PDB) so far. A crystal structure of Anopheles gambiae AChE of the malaria mosquito was recently reported with a low structure resolution of 3.4 Å that may not be exploitable for docking study [61]. Another crystal structure of Anopheles gambiae AChE of the malaria insecticide-resistant mosquito harboring a G119S mutation was deposited with a better resolution (2.26 Å) [54].…”

Section: Molecular Modelingmentioning

confidence: 99%

Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation

et al. 2020

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Malaria, affecting all continents, remains one of the life-threatening diseases introduced by parasites that are transmitted to humans through the bites of infected Anopheles mosquitoes. Although insecticides are currently used to reduce malaria transmission, their safety concern for living systems, as well as the environment, is a growing problem. Therefore, the discovery of novel, less toxic, and environmentally safe molecules to effectively combat the control of these vectors is in high demand. In order to identify new potential larvicidal agents, a series of 2-aryl-1,2-dihydroquinazolin-4-one derivatives were synthesized and evaluated for their larvicidal activity against Anopheles arabiensis. The in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the compounds were also investigated and most of the derivatives possessed a favorable ADMET profile. Computational modeling studies of the title compounds demonstrated a favorable binding interaction against the acetylcholinesterase enzyme molecular target. Thus, 2-aryl-1,2-dihydroquinazolin-4-ones were identified as a novel class of Anopheles arabiensis insecticides which can be used as lead molecules for the further development of more potent and safer larvicidal agents for treating malaria.

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Crystal structure of acetylcholinesterase catalytic subunits of the malaria vector Anopheles gambiae

Cited by 23 publications

References 15 publications

A Second Look at the Crystal Structures of Drosophila melanogaster Acetylcholinesterase in Complex with Tacrine Derivatives Provides Insights Concerning Catalytic Intermediates and the Design of Specific Insecticides

A Second Look at the Crystal Structures of Drosophila melanogaster Acetylcholinesterase in Complex with Tacrine Derivatives Provides Insights Concerning Catalytic Intermediates and the Design of Specific Insecticides

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation

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