Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors.
Olsen JA
,
Ahring PK
,
Kastrup JS
,
Gajhede M
,
Balle T
.
???displayArticle.abstract???
Modulation of Cys loop receptor ion channels is a proven drug discovery strategy, but many underlying mechanisms of the mode of action are poorly understood. We report the x-ray structure of the acetylcholine-binding protein from Lymnaea stagnalis with NS9283, a stoichiometry selective positive modulator that targets the α4-α4 interface of α4β2 nicotinic acetylcholine receptors (nAChRs). Together with homology modeling, mutational data, quantum mechanical calculations, and pharmacological studies on α4β2 nAChRs, the structure reveals a modulator binding mode that overlaps the α4-α4 interface agonist (acetylcholine)-binding site. Analysis of contacts to residues known to govern agonist binding and function suggests that modulation occurs by an agonist-like mechanism. Selectivity for α4-α4 over α4-β2 interfaces is determined mainly by steric restrictions from Val-136 on the β2-subunit and favorable interactions between NS9283 and His-142 at the complementary side of α4. In the concentration ranges where modulation is observed, its selectivity prevents NS9283 from directly activating nAChRs because activation requires coordinated action from more than one interface. However, we demonstrate that in a mutant receptor with one natural and two engineered α4-α4 interfaces, NS9283 is an agonist. Modulation via extracellular binding sites is well known for benzodiazepines acting at γ-aminobutyric acid type A receptors. Like NS9283, benzodiazepines increase the apparent agonist potency with a minimal effect on efficacy. The shared modulatory profile along with a binding site located in an extracellular subunit interface suggest that modulation via an agonist-like mechanism may be a common mechanism of action that potentially could apply to Cys loop receptors beyond the α4β2 nAChRs.
Bergmann,
A unified model of the GABA(A) receptor comprising agonist and benzodiazepine binding sites.
2013, Pubmed
Bergmann,
A unified model of the GABA(A) receptor comprising agonist and benzodiazepine binding sites.
2013,
Pubmed
Bertrand,
Allosteric modulation of nicotinic acetylcholine receptors.
2007,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed
D'hoedt,
Nicotinic acetylcholine receptors: an overview on drug discovery.
2009,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Gallivan,
Can lone pairs bind to a pi system? The water...hexafluorobenzene interaction.
1999,
Pubmed
Gotti,
Brain nicotinic acetylcholine receptors: native subtypes and their relevance.
2006,
Pubmed
Grupe,
Unravelling the mechanism of action of NS9283, a positive allosteric modulator of (α4)3(β2)2 nicotinic ACh receptors.
2013,
Pubmed
Hansen,
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
2007,
Pubmed
Harpsøe,
Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors.
2011,
Pubmed
Hogg,
Nicotinic acetylcholine receptors as drug targets.
2004,
Pubmed
Jacobson,
On the role of the crystal environment in determining protein side-chain conformations.
2002,
Pubmed
Lee,
α4β2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of α4β2 nAChR agonists in pain.
2011,
Pubmed
Lester,
Cys-loop receptors: new twists and turns.
2004,
Pubmed
Li,
Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog.
2006,
Pubmed
Löscher,
How theories evolved concerning the mechanism of action of barbiturates.
2012,
Pubmed
Miller,
Binding, activation and modulation of Cys-loop receptors.
2010,
Pubmed
Mirza,
NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy.
2008,
Pubmed
Neubig,
International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology.
2003,
Pubmed
Nielsen,
Novel potent ligands for the central nicotinic acetylcholine receptor: synthesis, receptor binding, and 3D-QSAR analysis.
2000,
Pubmed
Olsen,
Molecular recognition of the neurotransmitter acetylcholine by an acetylcholine binding protein reveals determinants of binding to nicotinic acetylcholine receptors.
2014,
Pubmed
Olsen,
Two distinct allosteric binding sites at α4β2 nicotinic acetylcholine receptors revealed by NS206 and NS9283 give unique insights to binding activity-associated linkage at Cys-loop receptors.
2013,
Pubmed
,
Xenbase
Pandya,
Allosteric modulators of the α4β2 subtype of neuronal nicotinic acetylcholine receptors.
2011,
Pubmed
Rayes,
Number and locations of agonist binding sites required to activate homomeric Cys-loop receptors.
2009,
Pubmed
Rohde,
Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine α4β2 receptors: unique role of halogen bonding revealed.
2012,
Pubmed
Rudolph,
Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes.
2011,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Seo,
The positive allosteric modulator morantel binds at noncanonical subunit interfaces of neuronal nicotinic acetylcholine receptors.
2009,
Pubmed
,
Xenbase
Shahsavar,
Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHβE suggests a unique mode of antagonism.
2012,
Pubmed
Shen,
Statistical potential for assessment and prediction of protein structures.
2006,
Pubmed
Sigel,
Structure, function, and modulation of GABA(A) receptors.
2012,
Pubmed
Talley,
Atomic interactions of neonicotinoid agonists with AChBP: molecular recognition of the distinctive electronegative pharmacophore.
2008,
Pubmed
Taly,
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
2009,
Pubmed
Timmermann,
An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.
2007,
Pubmed
,
Xenbase
Timmermann,
Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.
2012,
Pubmed
,
Xenbase
Twyman,
Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital.
1989,
Pubmed
Ussing,
Synthesis, pharmacology, and biostructural characterization of novel α4β2 nicotinic acetylcholine receptor agonists.
2013,
Pubmed
,
Xenbase
Williams,
Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.
2011,
Pubmed
Winn,
Overview of the CCP4 suite and current developments.
2011,
Pubmed
Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase
Zwart,
Automated structure solution with the PHENIX suite.
2008,
Pubmed
