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Chembiochem
2014 Feb 10;153:413-24. doi: 10.1002/cbic.201300577.
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Acetylcholine promotes binding of α-conotoxin MII at α3 β2 nicotinic acetylcholine receptors.
Sambasivarao SV
,
Roberts J
,
Bharadwaj VS
,
Slingsby JG
,
Rohleder C
,
Mallory C
,
Groome JR
,
McDougal OM
,
Maupin CM
.
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α-Conotoxin MII (α-CTxMII) is a 16-residue peptide with the sequence GCCSNPVCHLEHSNLC, containing Cys2-Cys8 and Cys3-Cys16 disulfide bonds. This peptide, isolated from the venom of the marine cone snail Conus magus, is a potent and selective antagonist of neuronal nicotinic acetylcholine receptors (nAChRs). To evaluate the impact of channel-ligand interactions on ligand-binding affinity, homology models of the heteropentameric α3β2-nAChR were constructed. The models were created in MODELLER with the aid of experimentally characterized structures of the Torpedo marmorata-nAChR (Tm-nAChR, PDB ID: 2BG9) and the Aplysia californica-acetylcholine binding protein (Ac-AChBP, PDB ID: 2BR8) as templates for the α3- and β2-subunit isoforms derived from rat neuronal nAChR primary amino acid sequences. Molecular docking calculations were performed with AutoDock to evaluate interactions of the heteropentameric nAChR homology models with the ligands acetylcholine (ACh) and α-CTxMII. The nAChR homology models described here bind ACh with binding energies commensurate with those of previously reported systems, and identify critical interactions that facilitate both ACh and α-CTxMII ligand binding. The docking calculations revealed an increased binding affinity of the α3β2-nAChR for α-CTxMII with ACh bound to the receptor, and this was confirmed through two-electrode voltage clamp experiments on oocytes from Xenopus laevis. These findings provide insights into the inhibition and mechanism of electrostatically driven antagonist properties of the α-CTxMIIs on nAChRs.
Albuquerque,
Mammalian nicotinic acetylcholine receptors: from structure to function.
2009, Pubmed
Albuquerque,
Mammalian nicotinic acetylcholine receptors: from structure to function.
2009,
Pubmed
Anand,
Neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes have a pentameric quaternary structure.
1991,
Pubmed
,
Xenbase
Arias,
Topology of ligand binding sites on the nicotinic acetylcholine receptor.
1997,
Pubmed
Arias,
Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors.
2000,
Pubmed
Azam,
Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors.
2009,
Pubmed
Bharadwaj,
Insights into the glycyl radical enzyme active site of benzylsuccinate synthase: a computational study.
2013,
Pubmed
Blum,
Nicotinic pharmacophore: the pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH.
2010,
Pubmed
,
Xenbase
Bordia,
Nigrostriatal damage preferentially decreases a subpopulation of alpha6beta2* nAChRs in mouse, monkey, and Parkinson's disease striatum.
2007,
Pubmed
Bowie,
A method to identify protein sequences that fold into a known three-dimensional structure.
1991,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Bullock,
DockoMatic 2.0: high throughput inverse virtual screening and homology modeling.
2013,
Pubmed
Bullock,
Dockomatic - automated ligand creation and docking.
2010,
Pubmed
Cartier,
A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors.
1996,
Pubmed
,
Xenbase
Cederholm,
Gating mechanisms in Cys-loop receptors.
2009,
Pubmed
Celie,
Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant.
2005,
Pubmed
,
Xenbase
Celie,
Crystal structure of acetylcholine-binding protein from Bulinus truncatus reveals the conserved structural scaffold and sites of variation in nicotinic acetylcholine receptors.
2005,
Pubmed
Chatrenet,
Photoactivatable agonist of the nicotinic acetylcholine receptor: potential probe to characterize the structural transitions of the acetylcholine binding site in different states of the receptor.
1992,
Pubmed
Cheng,
Channel opening motion of alpha7 nicotinic acetylcholine receptor as suggested by normal mode analysis.
2006,
Pubmed
Chi,
Solution conformation of a neuronal nicotinic acetylcholine receptor antagonist alpha-conotoxin OmIA that discriminates alpha3 vs. alpha6 nAChR subtypes.
2006,
Pubmed
Cooper,
Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor.
1991,
Pubmed
Curtis,
A new look at the neuronal nicotinic acetylcholine receptor pharmacophore.
2000,
Pubmed
,
Xenbase
Davis,
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids.
2007,
Pubmed
Davis,
MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes.
2004,
Pubmed
Dray,
Neuropathic pain: emerging treatments.
2008,
Pubmed
Dutertre,
Computational approaches to understand alpha-conotoxin interactions at neuronal nicotinic receptors.
2004,
Pubmed
Dutertre,
Determination of alpha-conotoxin binding modes on neuronal nicotinic acetylcholine receptors.
2004,
Pubmed
Dutertre,
AChBP-targeted alpha-conotoxin correlates distinct binding orientations with nAChR subtype selectivity.
2007,
Pubmed
,
Xenbase
Dwoskin,
Competitive neuronal nicotinic receptor antagonists: a new direction for drug discovery.
2001,
Pubmed
Everhart,
Determinants of potency on alpha-conotoxin MII, a peptide antagonist of neuronal nicotinic receptors.
2004,
Pubmed
,
Xenbase
Gehrmann,
Solution structure of alpha-conotoxin ImI by 1H nuclear magnetic resonance.
1999,
Pubmed
Haddadian,
In silico models for the human alpha4beta2 nicotinic acetylcholine receptor.
2008,
Pubmed
Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed
Hansen,
Structural and ligand recognition characteristics of an acetylcholine-binding protein from Aplysia californica.
2004,
Pubmed
Hu,
The 1.1 A crystal structure of the neuronal acetylcholine receptor antagonist, alpha-conotoxin PnIA from Conus pennaceus.
1996,
Pubmed
Itier,
Neuronal nicotinic receptors: from protein structure to function.
2001,
Pubmed
Johnson,
NCBI BLAST: a better web interface.
2008,
Pubmed
Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed
Kasheverov,
Interaction of alpha-conotoxin ImII and its analogs with nicotinic receptors and acetylcholine-binding proteins: additional binding sites on Torpedo receptor.
2009,
Pubmed
,
Xenbase
Lemoine,
Ligand-gated ion channels: new insights into neurological disorders and ligand recognition.
2012,
Pubmed
Le Novère,
Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites.
2002,
Pubmed
Livett,
Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor.
2006,
Pubmed
Lloyd,
Neuronal nicotinic acetylcholine receptors as novel drug targets.
2000,
Pubmed
Luo,
Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel microsite of the alpha3beta2 nicotinic receptor.
2010,
Pubmed
,
Xenbase
Maslennikov,
NMR spatial structure of alpha-conotoxin ImI reveals a common scaffold in snail and snake toxins recognizing neuronal nicotinic acetylcholine receptors.
1999,
Pubmed
McCallum,
Decrease in alpha3*/alpha6* nicotinic receptors but not nicotine-evoked dopamine release in monkey brain after nigrostriatal damage.
2005,
Pubmed
McDougal,
pKa determination of histidine residues in α-conotoxin MII peptides by 1H NMR and constant pH molecular dynamics simulation.
2013,
Pubmed
McIntosh,
Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors.
2004,
Pubmed
,
Xenbase
Melo,
Fold assessment for comparative protein structure modeling.
2007,
Pubmed
Meltzer,
Electrostatic steering at acetylcholine binding sites.
2006,
Pubmed
Michel,
Specific needs of dopamine neurons for stimulation in order to survive: implication for Parkinson disease.
2013,
Pubmed
Morris,
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.
2009,
Pubmed
Nicke,
Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes.
2004,
Pubmed
Olivera,
Speciation of cone snails and interspecific hyperdivergence of their venom peptides. Potential evolutionary significance of introns.
1999,
Pubmed
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Quik,
Striatal alpha6* nicotinic acetylcholine receptors: potential targets for Parkinson's disease therapy.
2006,
Pubmed
Quik,
α6β2* and α4β2* nicotinic acetylcholine receptors as drug targets for Parkinson's disease.
2011,
Pubmed
Rogers,
Structure-activity relationships in a peptidic alpha7 nicotinic acetylcholine receptor antagonist.
2000,
Pubmed
Role,
Nicotinic receptors in the development and modulation of CNS synapses.
1996,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Schapira,
Structural model of nicotinic acetylcholine receptor isotypes bound to acetylcholine and nicotine.
2002,
Pubmed
Shon,
A noncompetitive peptide inhibitor of the nicotinic acetylcholine receptor from Conus purpurascens venom.
1997,
Pubmed
Shon,
Three-dimensional solution structure of alpha-conotoxin MII, an alpha3beta2 neuronal nicotinic acetylcholine receptor-targeted ligand.
1997,
Pubmed
Sine,
The nicotinic receptor ligand binding domain.
2002,
Pubmed
Talley,
Alpha-conotoxin OmIA is a potent ligand for the acetylcholine-binding protein as well as alpha3beta2 and alpha7 nicotinic acetylcholine receptors.
2006,
Pubmed
,
Xenbase
Ulens,
Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP.
2006,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Wada,
Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat.
1989,
Pubmed
,
Xenbase
Yeh,
Neuronal nicotinic acetylcholine receptor alpha3 subunit protein in rat brain and sympathetic ganglion measured using a subunit-specific antibody: regional and ontogenic expression.
2001,
Pubmed
Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed
