Inhibition Mechanism of the Acetylcholine Receptor by α-Neurotoxins as Revealed by Normal-Mode Dynamics

Samson, Abraham O.; Levitt, Michael

doi:10.1021/bi702272j

Cited by 34 publications

(29 citation statements)

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“…This global quaternary twist motion reasonably accounted for the available experimental data on the gating process (135). This analysis was soon confirmed and extended by several groups (136,137). Yet we were still missing the relevant X-ray structural information on the whole receptor.…”

Section: The Quaternary Twist Mechanismsupporting

confidence: 76%

Allosteric Receptors: From Electric Organ to Cognition

Changeux

2010

Annu. Rev. Pharmacol. Toxicol.

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This autobiography covers the past 50 years beginning with the development of the concept of allosteric proteins and its application to pharmacological receptors. It continues with the identification of the nicotinic acetylcholine receptor, the discovery of its molecular organization, the structure of the acetylcholine-binding site and of the ion channel, and the demonstration of its allosteric transitions. The article then traces the origins of the concept of allosteric modulator and its consequences in pharmacology. It proceeds with the theory of selective stabilization of synapses and with experimental studies carried out on the contribution of the nicotinic receptor in the morphogenesis of the neuromuscular junction. The knowledge acquired with the nicotinic receptor is further exploited to reach higher levels of brain organization, and the contribution of nicotinic receptors to the action of nicotine on reward and cognition is explored, in particular, using a novel experimental strategy that combines nicotinic receptor genes knock-out and stereotaxic gene re-expression. Theoretical models of cognitive functions are proposed that link the molecular to the cognitive level. The report ends with a discussion on nicotinic receptors and the pharmacology of the future.

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Section: The Quaternary Twist Mechanismsupporting

confidence: 76%

Allosteric Receptors: From Electric Organ to Cognition

Changeux

2010

Annu. Rev. Pharmacol. Toxicol.

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“…Low-frequency normal modes of biomolecular systems have been identified with functional motions, e.g., gating motions of nicotinic acetylcholine receptors (29)(30)(31)(32) and acid-sensing ion channel 1 (ASIC1) (33). Here we treated zfP2X4R by the elastic network model (34), in which each atom was elastically connected to neighboring atoms.…”

Section: Resultsmentioning

confidence: 99%

Gating mechanism of a P2X4 receptor developed from normal mode analysis and molecular dynamics simulations

Dong

Zhou

2012

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

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P2X receptors are trimeric ATP-gated cation channels participating in diverse physiological processes. How ATP binding triggers channel opening remains unclear. Here the gating mechanism of a P2X receptor was studied by normal mode analysis and molecular dynamics (MD) simulations. Based on the resting-state crystal structure, a normal mode involving coupled motions of three β-strands (β1, β13, and β14) at the trimeric interface of the ligandbinding ectodomain and the pore-lining helix (TM2) in the transmembrane domain (TMD) was identified. The resulting widening of the fenestrations above the TMD and opening of the transmembrane pore produce known signatures of channel activation. In MD simulations, ATP was initially placed in the putative binding pocket (defined by four charged residues located in β1, β13 and β14) in two opposite orientations, with the adenine either proximal or distal to the TMD. In the proximal orientation, the triphosphate group extends outward to draw in the four charged residues, leading to closure of β13/β14 toward β1. The adenine ring, wedged between β1 and β13, acts as a fulcrum for the β14 lever, turning a modest closure around the triphosphate group into significant opening of the pre-TM2 loop. The motions of these β-strands are similar to those in the putative channel-activation normal mode. In the distal orientation, the ATP stabilizes the trimeric interface and the closure of the pre-TM2 loop, possibly representing desensitization. Our computational studies produced the first complete model, supported by experimental data, for how ATP binding triggers activation of a P2X receptor.antagonist design | ATP binding mode | channel-activation mechanism | ligand-gated ion channels P 2X receptors (P2XRs) are a family of ligand-gated nonselective cation channels activated by extracelluar ATP (1). Distributed throughout the human body, they participate in diverse physiological processes such as synaptic transmission, response to inflammation, and pain sensation, and thus are potential drug targets (2-7). Seven subtypes of P2XRs, P2XR1 to P2X7R, have been identified in mammals. They assemble to form functional homo-or hetero-trimeric channels (8), distinguishing them from the better-studied tetrameric and pentameric ligand-gated ionchannel families. The recent crystal structure of zebrafish P2X4 receptor (zfP2X4R) in the resting state represents a major advance in understanding the structure and function of P2XR ion channels (9). Each subunit of zfP2X4R contains two transmembrane helices (TM1 and TM2), which link the intracellular amino and carboxyl termini to the large ligand-binding ectodomain (Fig. 1). In the ectodomain, each subunit consists of 4 α-helices and 14 β-strands (β1-β14). β1 and β14 are connected to TM1 and TM2, respectively.Studies based on mutagenesis have identified several highly conserved ectodomain residues as involved in ATP binding (10-18). The conserved residues include four cationic ones: K70 and K72 on β1, R298 on β13, and K316 on β14 (10,19,20). Aromatic and polar r...

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“…Because it is difficult to simulate these time scales using molecular dynamics, normal mode analysis has been used to look at long time-scale collective motions (Bertaccini et al, 2005). Briefly, normal mode analysis starts by rendering each amino acid in a protein as a weighted sphere and connecting the spheres with springs of variable force constants Tirion, 1996;Hinsen, 1998;Delarue and Sanejouand, 2002;Lindahl et al, 2006;Bertaccini et al, 2008;Samson and Levitt, 2008). An analysis of all the vibrational modes in this spherespring assembly can be accomplished in a matter of hours, after which the results are sorted by frequency and amplitude (Lindahl et al, 2006).…”

Section: B Elastic Network Calculationsmentioning

confidence: 99%