The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Igor F. Tsigelny - One of the best experts on this subject based on the ideXlab platform.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Hitoshi Osaka, Brian E. Molles, S Malanz, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Siobhan Malany, Hitoshi Osaka, Brian E. Molles, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (αγαδβ), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the αγ and αδ subunit interfaces. By interchanging residues on the γ and δ subunits through mutagenesis, and ascertaining how they interact with the α subunit, determinants forming the binding sites can be delineated. The α-conotoxins show a 10,000-fold preference for the αδ over αγ subunit interface with αɛ falling in between. The waglerins show a 2,000-fold preference for αɛ over the αγ and αδ interfaces. Finally, the α-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the αγ and αδ interfaces over αɛ. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:Abstract The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (αγαδβ), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the αγ and αδ interfaces. By interchanging residues on the γ and δ subunits, and ascertaining how they interact with the α-subunit, determinants forming the binding sites can be delineated. The α-conotoxins, which contain two disulfide loops and 12–14 amino acids, show a 10 000-fold preference for the αγ over the αγ subunit interface with αe falling between the two. The waglerins, as 22–24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for αe over the αγ and αδ interfaces. Finally, the 6700 Da short α-neurotoxin from N. mossambica mossambica shows a 10 000-fold preference for the αγ and αδ interfaces over αe. Selective mutagenesis enables one to also distinguish α-neurotoxin binding at the αγ and αδ subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
Palmer Taylor - One of the best experts on this subject based on the ideXlab platform.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Hitoshi Osaka, Brian E. Molles, S Malanz, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Siobhan Malany, Hitoshi Osaka, Brian E. Molles, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (αγαδβ), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the αγ and αδ subunit interfaces. By interchanging residues on the γ and δ subunits through mutagenesis, and ascertaining how they interact with the α subunit, determinants forming the binding sites can be delineated. The α-conotoxins show a 10,000-fold preference for the αδ over αγ subunit interface with αɛ falling in between. The waglerins show a 2,000-fold preference for αɛ over the αγ and αδ interfaces. Finally, the α-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the αγ and αδ interfaces over αɛ. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:Abstract The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (αγαδβ), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the αγ and αδ interfaces. By interchanging residues on the γ and δ subunits, and ascertaining how they interact with the α-subunit, determinants forming the binding sites can be delineated. The α-conotoxins, which contain two disulfide loops and 12–14 amino acids, show a 10 000-fold preference for the αγ over the αγ subunit interface with αe falling between the two. The waglerins, as 22–24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for αe over the αγ and αδ interfaces. Finally, the 6700 Da short α-neurotoxin from N. mossambica mossambica shows a 10 000-fold preference for the αγ and αδ interfaces over αe. Selective mutagenesis enables one to also distinguish α-neurotoxin binding at the αγ and αδ subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
Steven M. Sine - One of the best experts on this subject based on the ideXlab platform.
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end plate acetylcholine Receptor Structure mechanism pharmacology and disease
Physiological Reviews, 2012Co-Authors: Steven M. SineAbstract:The synapse is a localized neurohumoral contact between a neuron and an effector cell and may be considered the quantum of fast intercellular communication. Analogously, the postsynaptic neurotransmitter Receptor may be considered the quantum of fast chemical to electrical transduction. Our understanding of postsynaptic Receptors began to develop about a hundred years ago with the demonstration that electrical stimulation of the vagus nerve released acetylcholine and slowed the heart beat. During the past 50 years, advances in understanding postsynaptic Receptors increased at a rapid pace, owing largely to studies of the acetylcholine Receptor (AChR) at the motor endplate. The endplate AChR belongs to a large superfamily of neurotransmitter Receptors, called Cys-loop Receptors, and has served as an exemplar Receptor for probing fundamental Structures and mechanisms that underlie fast synaptic transmission in the central and peripheral nervous systems. Recent studies provide an increasingly detailed picture of the Structure of the AChR and the symphony of molecular motions that underpin its remarkably fast and efficient chemoelectrical transduction.
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Recent advances in Cys-loop Receptor Structure and function.
Nature, 2006Co-Authors: Steven M. Sine, Andrew G. EngelAbstract:Throughout the nervous system, moment-to-moment communication relies on postsynaptic Receptors to detect neurotransmitters and change the membrane potential. For the Cys-loop superfamily of Receptors, recent structural data have catalysed a leap in our understanding of the three steps of chemical-to-electrical transduction: neurotransmitter binding, communication between the binding site and the barrier to ions, and opening and closing of the barrier. The emerging insights might be expected to explain how mutations of Receptors cause neurological disease, but the opposite is generally true. Namely, analyses of disease-causing mutations have clarified Receptor Structure-function relationships as well as mechanisms governing the postsynaptic response.
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Molecular insights into acetylcholine Receptor Structure and function revealed by mutations causing congenital myasthenic syndromes
Molecular Insights into Ion Channel Biology in Health and Disease, 2004Co-Authors: Steven M. Sine, Andrew G. Engel, Hai Long Wang, Kinji OhnoAbstract:Publisher Summary This chapter provides molecular insights into acetylcholine Receptor Structure and function revealed by mutations causing congenital myasthenic syndromes (CMS). The investigation of CMS proceeds from a generic clinical diagnosis to defining the morphologic and electrophysiologic phenotype. If these studies point to a candidate gene whose sequence is known, then mutation analysis becomes feasible. In addition, if a mutation in a relevant protein is identified, then appropriate expression studies are designed. A generic clinical diagnosis of a CMS is based on the history of myasthenic symptoms from birth or early childhood, similarly affected relatives, a decremental electromyographic (EMG) response of the compound muscle fiber action potential on low-frequency (2–3 Hz) stimulation, and a negative test for anti-AChR antibodies. Some CMS cases, however, are sporadic or present in later life and the decremental EMG response may not be present in all muscles or at all times. Conventional microelectrode studies on muscle specimens excised from origin to insertion readily reveal whether the defect of neuromuscular transmission is presynaptic, synaptic, or postsynaptic and define the factors that impair the safety margin of neuromuscular transmission.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:Abstract The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (αγαδβ), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the αγ and αδ interfaces. By interchanging residues on the γ and δ subunits, and ascertaining how they interact with the α-subunit, determinants forming the binding sites can be delineated. The α-conotoxins, which contain two disulfide loops and 12–14 amino acids, show a 10 000-fold preference for the αγ over the αγ subunit interface with αe falling between the two. The waglerins, as 22–24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for αe over the αγ and αδ interfaces. Finally, the 6700 Da short α-neurotoxin from N. mossambica mossambica shows a 10 000-fold preference for the αγ and αδ interfaces over αe. Selective mutagenesis enables one to also distinguish α-neurotoxin binding at the αγ and αδ subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
Brian E. Molles - One of the best experts on this subject based on the ideXlab platform.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Hitoshi Osaka, Brian E. Molles, S Malanz, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Siobhan Malany, Hitoshi Osaka, Brian E. Molles, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (αγαδβ), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the αγ and αδ subunit interfaces. By interchanging residues on the γ and δ subunits through mutagenesis, and ascertaining how they interact with the α subunit, determinants forming the binding sites can be delineated. The α-conotoxins show a 10,000-fold preference for the αδ over αγ subunit interface with αɛ falling in between. The waglerins show a 2,000-fold preference for αɛ over the αγ and αδ interfaces. Finally, the α-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the αγ and αδ interfaces over αɛ. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:Abstract The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (αγαδβ), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the αγ and αδ interfaces. By interchanging residues on the γ and δ subunits, and ascertaining how they interact with the α-subunit, determinants forming the binding sites can be delineated. The α-conotoxins, which contain two disulfide loops and 12–14 amino acids, show a 10 000-fold preference for the αγ over the αγ subunit interface with αe falling between the two. The waglerins, as 22–24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for αe over the αγ and αδ interfaces. Finally, the 6700 Da short α-neurotoxin from N. mossambica mossambica shows a 10 000-fold preference for the αγ and αδ interfaces over αe. Selective mutagenesis enables one to also distinguish α-neurotoxin binding at the αγ and αδ subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
Hitoshi Osaka - One of the best experts on this subject based on the ideXlab platform.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Hitoshi Osaka, Brian E. Molles, S Malanz, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Subunit interface selective toxins as probes of nicotinic acetylcholine Receptor Structure.
Pflugers Archiv : European journal of physiology, 2000Co-Authors: Palmer Taylor, Siobhan Malany, Hitoshi Osaka, Brian E. Molles, Igor F. TsigelnyAbstract:The pentametric assembly of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The Receptor from mammalian muscle, with its circular order of homologous subunits (αγαδβ), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the αγ and αδ subunit interfaces. By interchanging residues on the γ and δ subunits through mutagenesis, and ascertaining how they interact with the α subunit, determinants forming the binding sites can be delineated. The α-conotoxins show a 10,000-fold preference for the αδ over αγ subunit interface with αɛ falling in between. The waglerins show a 2,000-fold preference for αɛ over the αγ and αδ interfaces. Finally, the α-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the αγ and αδ interfaces over αɛ. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of Receptor Structure.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
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Toxins selective for subunit interfaces as probes of nicotinic acetylcholine Receptor Structure.
Journal of physiology Paris, 1998Co-Authors: Palmer Taylor, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Hitoshi Osaka, Steven M. Sine, Brian E. Molles, Naoya Sugiyama, Joseph J. Mcardle, Igor F. TsigelnyAbstract:Abstract The pentameric Structure of the nicotinic acetylcholine Receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The Receptor, with its circular order of homologous subunits (αγαδβ), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the αγ and αδ interfaces. By interchanging residues on the γ and δ subunits, and ascertaining how they interact with the α-subunit, determinants forming the binding sites can be delineated. The α-conotoxins, which contain two disulfide loops and 12–14 amino acids, show a 10 000-fold preference for the αγ over the αγ subunit interface with αe falling between the two. The waglerins, as 22–24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for αe over the αγ and αδ interfaces. Finally, the 6700 Da short α-neurotoxin from N. mossambica mossambica shows a 10 000-fold preference for the αγ and αδ interfaces over αe. Selective mutagenesis enables one to also distinguish α-neurotoxin binding at the αγ and αδ subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of Receptor Structure and conformation.
