Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor

Spurný, Radovan; Debaveye, Sarah; Farinha, Ana; Veys, Ken; Vos, Ann; Gossas, Thomas; Atack, John; Bertrand, Sonia; Bertrand, Daniel; Danielson, U. Helena; Tresadern, Gary; Ulens, Chris

doi:10.1073/pnas.1418289112

Cited by 101 publications

(108 citation statements)

References 37 publications

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“…6A). Using a fragmentbased screening approach, Spurny et al (54) discovered three allosteric binding sites in α7-AChBP, which are remote from the orthosteric binding site occupied by the agonist lobeline in these structures (yellow spheres, Fig. 6A), and also the agonist epibatidine (55) or the competitive antagonist α-bungarotoxin in other α7-AChBP cocrystal structures (56).…”

Section: Discussionmentioning

confidence: 99%

“…6A). This site was termed the "top site" and is involved in negative modulation of the α7 nAChR (54). The same fragment molecule also occupies an allosteric binding site that is located just below the orthosteric binding site and that was termed the "agonist subsite" (pink spheres, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The same fragment molecule also occupies an allosteric binding site that is located just below the orthosteric binding site and that was termed the "agonist subsite" (pink spheres, Fig. 6A) (54). This site corresponds to the ketamine binding site reported in the GLIC (57), where ketamine also binds just below the orthosteric agonist binding site and is involved in inhibition of GLIC (pink spheres, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Another fragment molecule, fragment 4, was identified that occupies an allosteric binding site accessible from the vestibule of the receptor and was termed the "vestibule site" (firebrick spheres, Fig. 6A) (54). This fragment is involved in negative modulation of the α7 nAChR (54).…”

Section: Discussionmentioning

confidence: 99%

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Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine

Nys

Wijckmans

Farinha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine. Unexpectedly, we do not find a chlorpromazine molecule in the channel pore of ELIC, but behind the β8-β9 loop in the extracellular ligand-binding domain. The β8-β9 loop is localized downstream from the neurotransmitter binding site and plays an important role in coupling of ligand binding to channel opening. In combination with electrophysiological recordings from ELIC cysteine mutants and a thiol-reactive derivative of chlorpromazine, we demonstrate that chlorpromazine binding at the β8-β9 loop is responsible for receptor inhibition. We further use molecular-dynamics simulations to support the X-ray data and mutagenesis experiments. Together, these data unveil an allosteric binding site in the extracellular ligand-binding domain of ELIC. Our results extend on previous observations and further substantiate our understanding of a multisite model for allosteric modulation of Cys-loop receptors.ligand-gated ion channel | X-ray crystallography | allosteric modulation | Cys-loop receptor | nicotinic acetylcholine receptor C hlorpromazine (CPZ) (Fig. 1), a phenothiazine-derived antipsychotic drug, was introduced in psychiatry in the early 1950s, revolutionizing the treatment of psychotic disorders (1, 2). The main mechanism of action of CPZ consists in the blockage of dopamine receptors (2-4), but the numerous side effects associated with this drug indicate that it interacts with other physiologically relevant targets. CPZ was indeed shown to interfere with several voltage-and ligand-gated channels: it inhibits neuronal voltage-gated K + channels (5-7), BK Ca channels (8), and the human α 1E subunit-mediated Ca 2+ channels (9); CPZ was also shown to inhibit GABAergic currents (10, 11), specifically through GABA A receptors (GABA A Rs) (12), and to inhibit serotonin type-3 receptors (5-HT 3 Rs) (13, 14) and nicotinic acetylcholine receptors (nAChRs) (15, 16), members of the Cys-loop receptor family.The Cys-loop receptor family is composed of membranespanning ligand-gated ion channels that are responsible for fast excitatory or inhibitory synaptic neurotransmission. They are composed of five identical or nonidentical subunits, each of them comprising an N-terminal extracellular domain, which contains the neurotransmitter binding site, four transmembrane helices, that when assembled allow ions to pass through the membrane, and an intracellular domain, responsible for channel conductance, receptor modulation, and trafficking (17, 18). Initial structural insight into the ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine

Nys

Wijckmans

Farinha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Exploring use of this drug, which enhances AChR release at the motor nerve terminal, in MuSK MG is supported by preclinical models, experience with congenital MG with MuSK mutations, and case reports [152,153]. Other endplate targets with potential therapeutic application in MG include agrin potentiators and positive allosteric modulators of the skeletal muscle AChR [154,155].…”

Section: Endplate-specific Factors and Muscle Contractilitymentioning

confidence: 99%

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

2016

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Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

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Cholinergics/Anticholinergics

Griffith¹,

Dukat²

2021

Burger's Medicinal Chemistry and Drug Discovery

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This article covers classes of drugs and chemicals that act directly on muscarinic and nicotinic cholinergic receptors as agonists, antagonist, or allosteric modulators, together with an overview of the structures of muscarinic and nicotinic receptors. A brief history of the use of the small molecules muscarine, nicotine, and atropine to differentiate nicotinic and muscarinic receptors both of which respond to the neurotransmitter acetylcholine. This followed by discussion of the physical nature of the muscarinic G‐protein‐coupled‐receptor and the ligand‐gated‐ion‐channel nicotinic receptor. The structure–activity relationships of muscarinic agonists and antagonists are discussed with reference to attempts to develop of drugs selective for one of the five muscarinic receptors. Muscarinic antagonists are employed to treat disease states such as asthma, COPD, and overactive bladder. Muscarinic agonists have potential in the treatment of Alzheimer's disease. The structure–activity relationships of agonists and antagonists of nicotinic receptors are presented. Nicotinic agonists have been employed to assist in smoking cessation and have potential in treating Alzheimer's disease. Nicotinic antagonists have primarily been employed as neuromuscular blockers in surgery. The use of both positive and negative allosteric modulators of both muscarinic and nicotinic are discussed.

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Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor

Cited by 101 publications

References 37 publications

Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine

Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

Cholinergics/Anticholinergics

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