Structural characterization of binding mode of smoking cessation drugs to nicotinic acetylcholine receptors through study of ligand complexes with acetylcholine-binding protein.

The Journal of Biological Chemistry
Prakash RucktooaTitia K Sixma

Abstract

Smoking cessation is an important aim in public health worldwide as tobacco smoking causes many preventable deaths. Addiction to tobacco smoking results from the binding of nicotine to nicotinic acetylcholine receptors (nAChRs) in the brain, in particular the α4β2 receptor. One way to aid smoking cessation is by the use of nicotine replacement therapies or partial nAChR agonists like cytisine or varenicline. Here we present the co-crystal structures of cytisine and varenicline in complex with Aplysia californica acetylcholine-binding protein and use these as models to investigate binding of these ligands binding to nAChRs. This analysis of the binding properties of these two partial agonists provides insight into differences with nicotine binding to nAChRs. A mutational analysis reveals that the residues conveying subtype selectivity in nAChRs reside on the binding site complementary face and include features extending beyond the first shell of contacting residues.

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Citations

Jul 16, 2013·Biochemical Pharmacology·Mieke NysChris Ulens
Jul 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Katarzyna KaczanowskaPalmer Taylor
Apr 8, 2016·International Journal for Parasitology. Drugs and Drug Resistance·Fudan ZhengRichard J Martin
Feb 5, 2015·ACS Chemical Neuroscience·Kerry L PriceSarah C R Lummis
Nov 18, 2015·Basic & Clinical Pharmacology & Toxicology·Azadeh ShahsavarThomas Balle
Aug 24, 2016·Expert Opinion on Drug Discovery·Miguel Reyes-Parada, Patricio Iturriaga-Vasquez
Dec 25, 2016·Journal of Structural and Functional Genomics·Clara Shionyu-MitsuyamaTsuyoshi Shirai
Feb 11, 2020·Acta Crystallographica. Section F, Structural Biology Communications·Samuel DavisWilliam N Hunter
Oct 28, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Juan Pablo González-GutiérrezMaría Carolina Zúñiga
Sep 14, 2019·Journal of the American Chemical Society·Annet E M BlomDennis A Dougherty
Mar 16, 2019·Science·Christopher J MagnusScott M Sternson

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Methods Mentioned

BETA
transfection
isothermal titration calorimetry
PISA
competition binding

Software Mentioned

BUSTER
MOSFLM
XSCALE
Graphpad Prism®
COOT
REDO script
XDS
PISA
GraphPad
CCP4

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