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.
Biochim Biophys Acta
2014 May 01;18385:1389-95. doi: 10.1016/j.bbamem.2013.12.018.
Show Gene links
Show Anatomy links
NMR structures of the human α7 nAChR transmembrane domain and associated anesthetic binding sites.
Bondarenko V, Mowrey DD, Tillman TS, Seyoum E, Xu Y, Tang P.
???displayArticle.abstract???
The α7 nicotinic acetylcholine receptor (nAChR), assembled as homomeric pentameric ligand-gated ion channels, is one of the most abundant nAChR subtypes in the brain. Despite its importance in memory, learning and cognition, no structure has been determined for the α7 nAChR TM domain, a target for allosteric modulators. Using solution state NMR, we determined the structure of the human α7 nAChR TM domain (PDB ID: 2MAW) and demonstrated that the α7 TM domain formed functional channels in Xenopus oocytes. We identified the associated binding sites for the anesthetics halothane and ketamine; the former cannot sensitively inhibit α7 function, but the latter can. The α7 TM domain folds into the expected four-helical bundle motif, but the intra-subunit cavity at the extracellular end of the α7 TM domain is smaller than the equivalent cavity in the α4β2 nAChRs (PDB IDs: 2LLY; 2LM2). Neither drug binds to the extracellular end of the α7 TM domain, but two halothane molecules or one ketamine molecule binds to the intracellular end of the α7 TM domain. Halothane and ketamine binding sites are partially overlapped. Ketamine, but not halothane, perturbed the α7 channel-gate residue L9'. Furthermore, halothane did not induce profound dynamics changes in the α7 channel as observed in α4β2. The study offers a novel high-resolution structure for the human α7 nAChR TM domain that is invaluable for developing α7-specific therapeutics. It also provides evidence to support the hypothesis: only when anesthetic binding perturbs the channel pore or alters the channel motion, can binding generate functional consequences.
Baxter,
Temperature dependence of 1H chemical shifts in proteins.
1997, Pubmed
Baxter,
Temperature dependence of 1H chemical shifts in proteins.
1997,
Pubmed Bertrand,
Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor: ligand interactions with distinct binding sites and evidence for a prominent role of the M2-M3 segment.
2008,
Pubmed
,
Xenbase Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed Bondarenko,
NMR structures of the transmembrane domains of the α4β2 nAChR.
2012,
Pubmed Bondarenko,
NMR resolved multiple anesthetic binding sites in the TM domains of the α4β2 nAChR.
2013,
Pubmed Bondarenko,
NMR structure of the transmembrane domain of the n-acetylcholine receptor beta2 subunit.
2010,
Pubmed Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed Canlas,
Anesthetic modulation of protein dynamics: insight from an NMR study.
2008,
Pubmed Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed Cheng,
Channel opening motion of alpha7 nicotinic acetylcholine receptor as suggested by normal mode analysis.
2006,
Pubmed Coates,
Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant alpha7 and alpha4beta2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes.
2001,
Pubmed
,
Xenbase Collins,
Nicotinic acetylcholine receptor transmembrane mutations convert ivermectin from a positive to a negative allosteric modulator.
2010,
Pubmed
,
Xenbase Cornilescu,
Protein backbone angle restraints from searching a database for chemical shift and sequence homology.
1999,
Pubmed Couturier,
A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is developmentally regulated and forms a homo-oligomeric channel blocked by alpha-BTX.
1990,
Pubmed
,
Xenbase Cui,
Four-alpha-helix bundle with designed anesthetic binding pockets. Part II: halothane effects on structure and dynamics.
2008,
Pubmed daCosta,
A lipid-dependent uncoupled conformation of the acetylcholine receptor.
2009,
Pubmed Dascal,
Voltage clamp recordings from Xenopus oocytes.
2001,
Pubmed
,
Xenbase Delaglio,
NMRPipe: a multidimensional spectral processing system based on UNIX pipes.
1995,
Pubmed Durrant,
POVME: an algorithm for measuring binding-pocket volumes.
2011,
Pubmed Flood,
Intravenous anesthetics differentially modulate ligand-gated ion channels.
2000,
Pubmed
,
Xenbase Folta-Stogniew,
Determination of molecular masses of proteins in solution: Implementation of an HPLC size exclusion chromatography and laser light scattering service in a core laboratory.
1999,
Pubmed Frueh,
Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase.
2008,
Pubmed Gill,
Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2011,
Pubmed
,
Xenbase Gotti,
Brain neuronal nicotinic receptors as new targets for drug discovery.
2006,
Pubmed Grønlien,
Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
2007,
Pubmed
,
Xenbase Güntert,
Torsion angle dynamics for NMR structure calculation with the new program DYANA.
1997,
Pubmed Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed Heeschen,
A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors.
2002,
Pubmed Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed Hilf,
X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
2008,
Pubmed Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase Jansen,
Modular design of Cys-loop ligand-gated ion channels: functional 5-HT3 and GABA rho1 receptors lacking the large cytoplasmic M3M4 loop.
2008,
Pubmed
,
Xenbase Koradi,
MOLMOL: a program for display and analysis of macromolecular structures.
1996,
Pubmed Kracun,
Influence of the M3-M4 intracellular domain upon nicotinic acetylcholine receptor assembly, targeting and function.
2008,
Pubmed Krause,
Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor.
1998,
Pubmed
,
Xenbase Lasalde,
Tryptophan substitutions at the lipid-exposed transmembrane segment M4 of Torpedo californica acetylcholine receptor govern channel gating.
1996,
Pubmed
,
Xenbase Lee,
Mutations in the M4 domain of Torpedo californica acetylcholine receptor dramatically alter ion channel function.
1994,
Pubmed
,
Xenbase Levin,
Nicotinic treatment for cognitive dysfunction.
2002,
Pubmed Li,
Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist.
2011,
Pubmed Li,
Site-specific mutations of nicotinic acetylcholine receptor at the lipid-protein interface dramatically alter ion channel gating.
1992,
Pubmed
,
Xenbase Marley,
A method for efficient isotopic labeling of recombinant proteins.
2001,
Pubmed Mayer,
Characterization of Ligand Binding by Saturation Transfer Difference NMR Spectroscopy.
1999,
Pubmed Mori,
Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons.
2001,
Pubmed
,
Xenbase Mowrey,
Insights into distinct modulation of α7 and α7β2 nicotinic acetylcholine receptors by the volatile anesthetic isoflurane.
2013,
Pubmed Mowrey,
Unresponsive correlated motion in alpha7 nAChR to halothane binding explains its functional insensitivity to volatile anesthetics.
2010,
Pubmed Nemecz,
Creating an α7 nicotinic acetylcholine recognition domain from the acetylcholine-binding protein: crystallographic and ligand selectivity analyses.
2011,
Pubmed Pan,
Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine.
2012,
Pubmed
,
Xenbase Prevost,
A locally closed conformation of a bacterial pentameric proton-gated ion channel.
2012,
Pubmed Rubboli,
Distribution of nicotinic receptors in the human hippocampus and thalamus.
1994,
Pubmed Smith,
The solubility of anesthetic gases in lipid bilayers.
1981,
Pubmed Sobolev,
SPACE: a suite of tools for protein structure prediction and analysis based on complementarity and environment.
2005,
Pubmed Strop,
Refractive index-based determination of detergent concentration and its application to the study of membrane proteins.
2005,
Pubmed Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed Unwin,
Gating movement of acetylcholine receptor caught by plunge-freezing.
2012,
Pubmed Valor,
Role of the large cytoplasmic loop of the alpha 7 neuronal nicotinic acetylcholine receptor subunit in receptor expression and function.
2002,
Pubmed
,
Xenbase Violet,
Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics.
1997,
Pubmed
,
Xenbase Wang,
Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
2003,
Pubmed Wevers,
Cellular distribution of nicotinic acetylcholine receptor subunit mRNAs in the human cerebral cortex as revealed by non-isotopic in situ hybridization.
1994,
Pubmed Wishart,
1H, 13C and 15N chemical shift referencing in biomolecular NMR.
1995,
Pubmed Xu,
NMR study of volatile anesthetic binding to nicotinic acetylcholine receptors.
2000,
Pubmed Yamakura,
Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine.
2000,
Pubmed
,
Xenbase Young,
Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2008,
Pubmed
,
Xenbase Zhang,
Volatile general anaesthetic actions on recombinant nACh alpha 7, 5-HT3 and chimeric nACh alpha 7-5-HT3 receptors expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
