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Allosterism

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Seiji Shinkai – One of the best experts on this subject based on the ideXlab platform.

  • Dynamic Rotational Oscillation of Cerium(IV) Bis(porphyrinate) and Its Control by Diamine Guest Binding with Positive Homotropic Allosterism
    European Journal of Organic Chemistry, 2007
    Co-Authors: Masato Ikeda, Masayuki Takeuchi, Yohei Kubo, Kousei Yamashita, Tomohiro Ikeda, Seiji Shinkai
    Abstract:

    We have synthesized a porphyrin oscillator (1) composed of cerium(IV) bis(porphyrinate) bearing four peripheral zinc(II) porphyrinates. The rotational oscillation frequency of the porphyrin was evaluated in solution with and without the presence of diamine guest 2 by variable temperature NMR spectroscopy. The results established that the rotational frequency can be controlled by added guest utilizing positive homotropic Allosterism. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

  • First successful molecular design of an artificial Lewis oligosaccharide binding system utilizing positive homotropic Allosterism.
    Journal of the American Chemical Society, 2001
    Co-Authors: Atsushi Sugasaki, Masato Ikeda, Kazunori Sugiyasu, And Masayuki Takeuchi, Seiji Shinkai
    Abstract:

    We have designed phenylboronic acid group appended Ce(IV) bis(porphyrinate) double decker 1 and meso−meso linked porphyrin 2, useful for the allosteric binding of biologically important saccharides, Lewis oligosaccharides. Compound 1 binds Lewis oligosaccharides in aqueous media because of the boronic acid−diol interaction, but the complexation event can occur only above the critical concentrations because of the sigmoidal [oligosaccharide] versus [complex] isotherm. Compound 1 has a sufficiently high affinity with Lewis oligosaccharides (K = 105−106 M-2) with Hill coefficients n of 1.8−2.0, and LewisX series and Lewisa series give opposite, symmetrical CD spectra. This is the first example of efficient binding of Lewis oligosaccharides to the artificial receptor, which has become possible by positive homotropic Allosterism.

  • Efficient Anion Binding to Cerium(IV) Bis(porphyrinate) Double Decker Utilizing Positive Homotropic Allosterism
    Chemistry Letters, 2001
    Co-Authors: Masashi Yamamoto, Masayuki Takeuchi, Masato Ikeda, Atsushi Sugasaki, Karine Frimat, Tony D. James, Seiji Shinkai
    Abstract:

    New cerium(IV) bis(porphyrinate) double decker bearing two pairs of anion binding sites was synthesized. This anion receptor can bind dianionic tartarate guest according to positive homotropic Allosterism. Analysis using the Hill equation afforded log K (association constant) = 9.33 [(mol dm−3)−2] and n (Hill coefficient) = 2.1 (± 0.1). This is the first example where “static” anion binding has been combined with the “dynamic” allosteric system.

Masato Ikeda – One of the best experts on this subject based on the ideXlab platform.

  • Dynamic Rotational Oscillation of Cerium(IV) Bis(porphyrinate) and Its Control by Diamine Guest Binding with Positive Homotropic Allosterism
    European Journal of Organic Chemistry, 2007
    Co-Authors: Masato Ikeda, Masayuki Takeuchi, Yohei Kubo, Kousei Yamashita, Tomohiro Ikeda, Seiji Shinkai
    Abstract:

    We have synthesized a porphyrin oscillator (1) composed of cerium(IV) bis(porphyrinate) bearing four peripheral zinc(II) porphyrinates. The rotational oscillation frequency of the porphyrin was evaluated in solution with and without the presence of diamine guest 2 by variable temperature NMR spectroscopy. The results established that the rotational frequency can be controlled by added guest utilizing positive homotropic Allosterism. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

  • First successful molecular design of an artificial Lewis oligosaccharide binding system utilizing positive homotropic Allosterism.
    Journal of the American Chemical Society, 2001
    Co-Authors: Atsushi Sugasaki, Masato Ikeda, Kazunori Sugiyasu, And Masayuki Takeuchi, Seiji Shinkai
    Abstract:

    We have designed phenylboronic acid group appended Ce(IV) bis(porphyrinate) double decker 1 and meso−meso linked porphyrin 2, useful for the allosteric binding of biologically important saccharides, Lewis oligosaccharides. Compound 1 binds Lewis oligosaccharides in aqueous media because of the boronic acid−diol interaction, but the complexation event can occur only above the critical concentrations because of the sigmoidal [oligosaccharide] versus [complex] isotherm. Compound 1 has a sufficiently high affinity with Lewis oligosaccharides (K = 105−106 M-2) with Hill coefficients n of 1.8−2.0, and LewisX series and Lewisa series give opposite, symmetrical CD spectra. This is the first example of efficient binding of Lewis oligosaccharides to the artificial receptor, which has become possible by positive homotropic Allosterism.

  • Efficient Anion Binding to Cerium(IV) Bis(porphyrinate) Double Decker Utilizing Positive Homotropic Allosterism
    Chemistry Letters, 2001
    Co-Authors: Masashi Yamamoto, Masayuki Takeuchi, Masato Ikeda, Atsushi Sugasaki, Karine Frimat, Tony D. James, Seiji Shinkai
    Abstract:

    New cerium(IV) bis(porphyrinate) double decker bearing two pairs of anion binding sites was synthesized. This anion receptor can bind dianionic tartarate guest according to positive homotropic Allosterism. Analysis using the Hill equation afforded log K (association constant) = 9.33 [(mol dm−3)−2] and n (Hill coefficient) = 2.1 (± 0.1). This is the first example where “static” anion binding has been combined with the “dynamic” allosteric system.

Masayuki Takeuchi – One of the best experts on this subject based on the ideXlab platform.

  • Dynamic Rotational Oscillation of Cerium(IV) Bis(porphyrinate) and Its Control by Diamine Guest Binding with Positive Homotropic Allosterism
    European Journal of Organic Chemistry, 2007
    Co-Authors: Masato Ikeda, Masayuki Takeuchi, Yohei Kubo, Kousei Yamashita, Tomohiro Ikeda, Seiji Shinkai
    Abstract:

    We have synthesized a porphyrin oscillator (1) composed of cerium(IV) bis(porphyrinate) bearing four peripheral zinc(II) porphyrinates. The rotational oscillation frequency of the porphyrin was evaluated in solution with and without the presence of diamine guest 2 by variable temperature NMR spectroscopy. The results established that the rotational frequency can be controlled by added guest utilizing positive homotropic Allosterism. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

  • Efficient Anion Binding to Cerium(IV) Bis(porphyrinate) Double Decker Utilizing Positive Homotropic Allosterism
    Chemistry Letters, 2001
    Co-Authors: Masashi Yamamoto, Masayuki Takeuchi, Masato Ikeda, Atsushi Sugasaki, Karine Frimat, Tony D. James, Seiji Shinkai
    Abstract:

    New cerium(IV) bis(porphyrinate) double decker bearing two pairs of anion binding sites was synthesized. This anion receptor can bind dianionic tartarate guest according to positive homotropic Allosterism. Analysis using the Hill equation afforded log K (association constant) = 9.33 [(mol dm−3)−2] and n (Hill coefficient) = 2.1 (± 0.1). This is the first example where “static” anion binding has been combined with the “dynamic” allosteric system.

  • Positive allosteric systems designed on dynamic supramolecular scaffolds: toward switching and amplification of guest affinity and selectivity.
    Accounts of chemical research, 2001
    Co-Authors: Seiji Shinkai, Masato Ikeda, And Atsushi Sugasaki, Masayuki Takeuchi
    Abstract:

    Positive homotropic Allosterism appears in important information transduction processes where chemical and physical signals are efficiently amplified. The phenomena are ubiquitous in nature, but the general methodology for the design of such allosteric systems is not yet established in an artificial system. This account reviews such artificial receptors that can bind guest ions and molecules in a positive allosteric manner and discusses what kinds of factors are indispensable as scaffolds in the design of this novel class of allosteric systems and what common factors are needed to realize the cooperativity. It has been shown that the scaffolds are mostly dynamic and are skillfully combined with the molecular recognition systems so that the subsequent guest binding can occur more favorably than the first guest binding. In addition, it has been suggested that positive homotropic Allosterism can be utilized as a new strategy to attain high guest selectivity and guest affinity which cannot be attained by conv…

Terry P. Kenakin – One of the best experts on this subject based on the ideXlab platform.

  • Allosteric Drug Effects
    Pharmacology in Drug Discovery and Development, 2017
    Co-Authors: Terry P. Kenakin
    Abstract:

    Abstract This chapter begins with a discussion of the characteristic properties of an allosteric molecule, namely saturability of effect (the allosteric modulation ends when the allosteric site is fully occupied), probe dependence (the allosteric effect of a given modulator can be different for different cobinding ligands) and the production of separate effects on the affinity and efficacy of the cobinding ligand. In addition, the strategies for identifying Allosterism and the reasons why this is relevant to drug discovery are featured. Specifically, these involve the unique therapeutic properties of allosteric modulators. Finally, the use of pharmacologic tools to quantify allosteric behavior of molecules in studies aimed at optimization of allosteric activity will be highlighted. Once Allosterism has been identified as a mechanism, then comparison of data to an allosteric model can be used to identify characteristic parameters of the effect.

  • Chapter 5 – Allosteric Drug Effects
    Pharmacology in Drug Discovery, 2012
    Co-Authors: Terry P. Kenakin
    Abstract:

    Publisher Summary In this chapter, the reader will learn about characteristic properties of allosteric molecules, how they interact with proteins and strategies for identifying Allosterism and the reasons why this is relevant to drug discovery. Specifically, these involve the unique therapeutic properties of allosteric modulators. This chapter describes the use of pharmacologic tools to quantify allosteric behavior of molecules for use in studies aimed at optimization of allosteric activity. Allosteric molecules can bind to virtually any site on the target protein and affect its activity; this greatly expands the possible therapeutic opportunities for a given target. Allosteric interactions on proteins such as receptors and ion channels occur through the binding of a molecule onto the protein to affect its free energy of conformation. Protein allostery describes the process of cooperation between binding sites, i.e., the binding of a molecule at one site on the protein alters the subsequent interaction of the protein with other molecules binding at other sites. Schematic diagram explains various possible effects of an allosteric modulator on the response to an agonist. Three properties of Allosterism are explained.

  • Refining efficacy: Allosterism and bias in G protein-coupled receptor signaling.
    Methods in molecular biology (Clifton N.J.), 2011
    Co-Authors: Louis M. Luttrell, Terry P. Kenakin
    Abstract:

    Receptors on the surface of cells function as conduits for information flowing between the external environment and the cell interior. Since signal transduction is based on the physical interaction of receptors with both extracellular ligands and intracellular effectors, ligand binding must produce conformational changes in the receptor that can be transmitted to the intracellular domains accessible to G proteins and other effectors. Classical models of G protprotein-coupled receptor (GPCR) signaling envision receptor conformations as highly constrained, wherein receptors exist in equilibrium between single “off” and “on” states distinguished by their ability to activate effectors, and ligands act by perturbing this equilibrium. In such models, ligands can be classified based upon two simple parameters; affinity and efficacy, and ligand activity is independent of the assay used to detect the response. However, it is clear that GPCRs assume multiple conformations, any number of which may be capable of interacting with a discrete subset of possible effectors. Both orthosteric ligands, molecules that occupy the natural ligand-binding pocket, and allosteric modulators, small molecules or proteins that contact receptors distant from the site of ligand binding, have the ability to alter the conformational equilibrium of a receptor in ways that affect its signaling output both qualitatively and quantitatively. In this context, efficacy becomes pluridimensional and ligand classification becomes assay dependent. A more complete description of ligand-receptor interaction requires the use of multiplexed assays of receptor activation and screening assays may need to be tailored to detect specific efficacy profiles.

Bharat Kumar Majhi – One of the best experts on this subject based on the ideXlab platform.

  • Allosterism in human complement component 5a (hC5a): a damper of C5a receptor (C5aR) signaling
    Journal of biomolecular structure & dynamics, 2015
    Co-Authors: Soumendra Rana, Amita Rani Sahoo, Bharat Kumar Majhi
    Abstract:

    The phenomena of Allosterism continues to advance the field of drug discovery, by illuminating gainful insights for many key processes, related to the structure–function relationships in proteins and enzymes, including the transmembrane G-protein coupled receptors (GPCRs), both in normal as well as in the disease states. However, Allosterism is completely unexplored in the native protprotein ligands, especially when a small covalent change significantly modulates the pharmacology of the protein ligands toward the signaling axes of the GPCRs. One such example is the human C5a (hC5a), the potent cationic anaphylatoxin that engages C5aR and C5L2 to elicit numerous immunological and non-immunological responses in humans. From the recently available structure–function data, it is clear that unlike the mouse C5a (mC5a), the hC5a displays conformational heterogeneity. However, the molecular basis of such conformational heterogeneity, otherwise Allosterism in hC5a and its precise contribution toward the overall C5aR …

  • Allosterism in human complement component 5a (hC5a): a damper of C5a receptor (C5aR) signaling
    , 2015
    Co-Authors: Soumendra Rana, Amita Rani Sahoo, Bharat Kumar Majhi
    Abstract:

    The phenomena of Allosterism continues to advance the field of drug discovery, by illuminating gainful insights for many key processes, related to the structure–function relationships in proteins and enzymes, including the transmembrane G-protein coupled receptors (GPCRs), both in normal as well as in the disease states. However, Allosterism is completely unexplored in the native protprotein ligands, especially when a small covalent change significantly modulates the pharmacology of the protein ligands toward the signaling axes of the GPCRs. One such example is the human C5a (hC5a), the potent cationic anaphylatoxin that engages C5aR and C5L2 to elicit numerous immunological and non-immunological responses in humans. From the recently available structure–function data, it is clear that unlike the mouse C5a (mC5a), the hC5a displays conformational heterogeneity. However, the molecular basis of such conformational heterogeneity, otherwise Allosterism in hC5a and its precise contribution toward the overall C5aR signaling is not known. This study attempts to decipher the functional role of Allosterism in hC5a, by exploring the inherent conformational dynamics in mC5a, hC5a and in its point mutants, including the proteolytic mutant des-Arg74-hC5a. Prima facie, the comparative molecular dynamics study, over total 500 ns, identifies Arg74-Tyr23 and Arg37-Phe51 “cation-π” pairs as the molecular “allosteric switches” on hC5a that potentially functions as a damper of C5aR signaling.