Covalent inhibition of hAChE by organophosphates causes homodimer dissociation through long-range allosteric effects

Blumenthal, Donald K.; Cheng, Xiaolin; Fajer, Mikolai; Ho, Kin‐Yip; Rohrer, Jacqueline; Gerlits, Oksana; Taylor, Palmer; Juneja, Puneet; Kovalevsky, Andrey; Radić, Zoran

doi:10.1016/j.jbc.2021.101007

Cited by 9 publications

(10 citation statements)

References 51 publications

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“…Solution-based, small angle X-ray scattering (SAXS) revealed promoted dissociation of the reversible hAChE homodimer, only in hAChE conjugates and complexes where the acyl pocket loop was observed to be distorted in the X-ray crystallographic structures (Blumenthal et al, 2021). While all individual steps in the mechanism of the dissociation have not been independently proven, it has been clearly demonstrated that ligand binding or conjugation to the active Ser at the base of the AChE active center gorge triggers the dissociation event at the intersubunit interface.…”

Section: S Tat I C C R Y S T a L L O G R A P H I C E Viden Ce Of Div...mentioning

confidence: 99%

Connectivity between surface and interior in catalytic subunits of acetylcholinesterases inferred from their X‐ray structures

Radić

2023

Journal of Neurochemistry

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Catalytic activity and function of acetylcholinesterase (AChE; EC 3.1.1.7) have been recognized and studied for over a century and its quaternary and primary structures for about half a century, and its tertiary structure has been known for about 33 years. Clear understanding of relationships between the structure and the function is still pending for this enzyme. Hundreds of crystallographic, static snapshots of AChEs from different sources reveal largely one general backbone conformation with narrow entry into the active center gorge, tightly fit to accept one acetylcholine (ACh) molecule, in contrast to its high catalytic turnover. This short review of available X‐ray structures of AChEs from electric ray Torpedo californica, mouse and human, finds some limited, yet consistent deviations in conformations of selected secondary structure elements of AChE relevant for its function. The observed conformational diversity of the acyl pocket loop of AChE, unlike the large Ω‐loop, appears consistent with structurally dynamic INS data and solution‐based SAXS experiments to explain its dominant role in controlling the size of the active center gorge opening, as well as connectivity between the immediate surroundings of the buried active Ser, and catalytically relevant sites on the AChE surface. image

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Section: S Tat I C C R Y S T a L L O G R A P H I C E Viden Ce Of Div...mentioning

confidence: 99%

Connectivity between surface and interior in catalytic subunits of acetylcholinesterases inferred from their X‐ray structures

Radić

2023

Journal of Neurochemistry

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“…Both effects compromise access of cationic pyridinium-based antidotes, such as HI6, towards conjugated phosphorus and its nucleophilic displacement that could reactivate inhibited hAChE. Subtle shifts in Cterminal α-helices were previously reported to be involved in the allosteric promotion of hAChE homodimer dissociation [14]. Interestingly, the conformation of the Ω-loop that serves as a "lid" of the active center gorge and also regulates the size of the active-center gorge opening was not affected in the POX-hAChE structure.…”

Section: Methodsmentioning

confidence: 99%

“…3992329. Last access on 18.10.2021), was used as shown earlier [3,14]. Among several PACCT 3 outputs, a bar chart of shifts of backbone Cα positions (given in Å) was used for comparison as a function of amino acid residue number.…”

Section: Methodsmentioning

confidence: 99%

“…This Java-based tool, available for download from Zenodo (www.ZENODO.org, DOI 10.5281/zenodo.3992329. Last accessed on 20 September 2021), was used as shown earlier [3,14]. Among several PACCT 3 outputs, a bar chart of shifts of backbone Cα positions (given in Å) was used for comparison as a function of amino acid residue number.…”

Section: Methodsmentioning

confidence: 99%

“…Structures of most OP-hAChE conjugates have been previously shown to be similar to that of native hAChE. Thus, we aimed to search for small but systematic deviations The exception is the structure of the POX-hAChE conjugate where OP binding triggered notable loop distortions [13] and consequential dissociation of the hAChE homodimer [14].…”

Section: Introductionmentioning

confidence: 99%

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Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition

Luedtke

Bojo

et al. 2021

Crystals

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Conformations of Cα backbones in X-ray structures of most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar to that of the native hAChE. One of the exceptions is the structure of the diethylphosphoryl-hAChE conjugate, where stabilization of a large ethoxy group into the acyl pocket (AP) of hAChE-triggered notable loop distortions and consequential dissociation of the hAChE homodimer. Recently, six X-ray structures of hAChE conjugated with large OP nerve agents of the A-type, Novichoks, have been deposited to PDB. In this study we analyzed backbone conformation shifts in those structures, as well as in OP-hAChE conjugates formed by Paraoxon, Soman, Tabun, and VX. A Java-based pairwise alpha carbon comparison tool (PACCT 3) was used for analysis. Surprisingly, despite the snug fit of large substituents on phosphorus, inside Novichok-conjugated hAChEs only minor conformational changes were detected in their backbones. Small magnitudes of observed changes were due to a 1.2–2.4 Å shift of the entire conjugated OP away from the AP. It thus appears that the small AP of AChEs can accommodate, without distortion, substituents of the size of ethoxy or butyryl groups, provided that conjugated OP is “pulled” away from the AP. This observation has practical consequences in the structure-based design of nucleophilic reactivation antidotes as well as in the definition of the AChE specificity that relies on the size of its AP.

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The mechanistic pathway induced by fenpropathrin toxicity: Oxidative stress, signaling pathway, and mitochondrial damage

Soliman,

Tohamy,

Prince

et al. 2024

J Biochem & Molecular Tox

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Fenpropathrin (FNP) is a kind of insecticide and acaricide known as pyrethroid. It is very effective, has a wide range of activities, and works quickly. Internationally, it is commonly considered the most powerful pyrethroid insecticide. Nevertheless, an increasing amount of data indicates a substantial link between Fenpropathrin and adverse effects on nontarget species, including liver toxicity, kidney toxicity, nerve damage, and reproductive toxicity. Oxidative stress plays a vital role in the toxicity of fenpropathrin, in addition to its mechanical mechanism. This study offers a thorough examination of the harmful effects of Fenpropathrin on oxidative and mitochondrial processes, as well as the signaling pathways involved in these effects. The significant impact of oxidative stress emphasizes the toxicity of Fenpropathrin.

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Covalent inhibition of hAChE by organophosphates causes homodimer dissociation through long-range allosteric effects

Cited by 9 publications

References 51 publications

Connectivity between surface and interior in catalytic subunits of acetylcholinesterases inferred from their X‐ray structures

Connectivity between surface and interior in catalytic subunits of acetylcholinesterases inferred from their X‐ray structures

Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition

The mechanistic pathway induced by fenpropathrin toxicity: Oxidative stress, signaling pathway, and mitochondrial damage

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