Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study

Terrone L. Rosenberry, Xavier Brazzolotto, Ian R. MacDonald, Marielle Wandhammer, Marie Trovaslet-Leroy, Sultan Darvesh, Florian Nachon

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.

Original languageEnglish (US)
Article number2098
JournalMolecules
Volume22
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Butyrylcholinesterase
Acetylcholinesterase
inhibitors
Ligands
ligands
Kinetics
kinetics
canyons
cholinergics
acetylcholine
neurotransmitters
Calorimetry
Propidium
supplements
linings
Substrate Specificity
Titration
Linings
Synaptic Transmission
titration

Keywords

  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Crystal structure
  • Isothermal titration calorimetry
  • Kinetics

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Rosenberry, T. L., Brazzolotto, X., MacDonald, I. R., Wandhammer, M., Trovaslet-Leroy, M., Darvesh, S., & Nachon, F. (2017). Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study. Molecules, 22(12), [2098]. https://doi.org/10.3390/molecules22122098

Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase : A crystallographic, kinetic and calorimetric study. / Rosenberry, Terrone L.; Brazzolotto, Xavier; MacDonald, Ian R.; Wandhammer, Marielle; Trovaslet-Leroy, Marie; Darvesh, Sultan; Nachon, Florian.

In: Molecules, Vol. 22, No. 12, 2098, 01.12.2017.

Research output: Contribution to journalArticle

Rosenberry, TL, Brazzolotto, X, MacDonald, IR, Wandhammer, M, Trovaslet-Leroy, M, Darvesh, S & Nachon, F 2017, 'Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study', Molecules, vol. 22, no. 12, 2098. https://doi.org/10.3390/molecules22122098
Rosenberry, Terrone L. ; Brazzolotto, Xavier ; MacDonald, Ian R. ; Wandhammer, Marielle ; Trovaslet-Leroy, Marie ; Darvesh, Sultan ; Nachon, Florian. / Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase : A crystallographic, kinetic and calorimetric study. In: Molecules. 2017 ; Vol. 22, No. 12.
@article{d8e5ba00166448f5b101ed61a583d964,
title = "Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study",
abstract = "Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.",
keywords = "Acetylcholinesterase, Butyrylcholinesterase, Crystal structure, Isothermal titration calorimetry, Kinetics",
author = "Rosenberry, {Terrone L.} and Xavier Brazzolotto and MacDonald, {Ian R.} and Marielle Wandhammer and Marie Trovaslet-Leroy and Sultan Darvesh and Florian Nachon",
year = "2017",
month = "12",
day = "1",
doi = "10.3390/molecules22122098",
language = "English (US)",
volume = "22",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "12",

}

TY - JOUR

T1 - Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase

T2 - A crystallographic, kinetic and calorimetric study

AU - Rosenberry, Terrone L.

AU - Brazzolotto, Xavier

AU - MacDonald, Ian R.

AU - Wandhammer, Marielle

AU - Trovaslet-Leroy, Marie

AU - Darvesh, Sultan

AU - Nachon, Florian

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.

AB - Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.

KW - Acetylcholinesterase

KW - Butyrylcholinesterase

KW - Crystal structure

KW - Isothermal titration calorimetry

KW - Kinetics

UR - http://www.scopus.com/inward/record.url?scp=85039771316&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039771316&partnerID=8YFLogxK

U2 - 10.3390/molecules22122098

DO - 10.3390/molecules22122098

M3 - Article

C2 - 29186056

AN - SCOPUS:85039771316

VL - 22

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 12

M1 - 2098

ER -