Channel Opening Motion of α7 Nicotinic Acetylcholine Receptor as Suggested by Normal Mode Analysis

Cheng, Xiaolin; Lu, Benzhuo; Grant, Barry J.; Law, Richard; McCammon, J. Andrew

doi:10.1016/j.jmb.2005.10.039

Cited by 106 publications

(162 citation statements)

References 60 publications

(98 reference statements)

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“…4D). This is the same motion seen in the first mode of normal mode analyses (14,16,18). We propose that the apo orange subunit is in the open conformation, with the swings of the C and F loops and concomitant tilt of the whole subunit leading to channel opening.…”

Section: Resultssupporting

confidence: 73%

“…In this ''quaternary twist'' model, the LBD rotates counterclockwise around the central axis, and the TMD rotates in the opposite direction (top view). This motion was also found to be the first mode in a normal mode analysis of McCammon and coworkers (16), but the latter authors built a structural model for channel activation by linearly combining the first and second modes. The resulting model appears to reproduce some aspects of the Unwin model.…”

mentioning

confidence: 84%

“…allostery ͉ spontaneous opening ͉ ligand-gated ion channel ͉ ligand binding N icotinic AChRs (nAChRs) are a well studied prototype for ligand-gated ion channels (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). nAChRs are pentamers consisting of either homo or hetero subunits.…”

mentioning

confidence: 99%

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Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Tjong

Zhou

2008

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

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Nicotinic AChRs (nAChRs) represent a paradigm for ligand-gated ion channels. Despite intensive studies over many years, our understanding of the mechanisms of activation and inhibition for nAChRs is still incomplete. Here, we present molecular dynamics (MD) simulations of the ␣7 nAChR ligand-binding domain, both in apo form and in ␣-Cobratoxin-bound form, starting from the respective homology models built on crystal structures of the acetylcholine-binding protein. The toxin-bound form was relatively stable, and its structure was validated by calculating mutational effects on the toxin-binding affinity. However, in the apo form, one subunit spontaneously moved away from the conformation of the other four subunits. This motion resembles what has been proposed for leading to channel opening. At the top, the C loop and the adjacent ␤7-␤8 loop swing downward and inward, whereas at the bottom, the F loop and the C terminus of ␤10 swing in the opposite direction. These swings appear to tilt the whole subunit clockwise. The resulting changes in solvent accessibility show strong correlation with experimental results by the substituted cysteine accessibility method upon addition of acetylcholine. Our MD simulation results suggest a mechanistic model in which the apo form, although predominantly sampling the ''closed'' state, can make excursions into the ''open'' state. The open state has high affinity for agonists, leading to channel activation, whereas the closed state upon distortion has high affinity for antagonists, leading to inhibition.allostery ͉ spontaneous opening ͉ ligand-gated ion channel ͉ ligand binding N icotinic AChRs (nAChRs) are a well studied prototype for ligand-gated ion channels (1-19). nAChRs are pentamers consisting of either homo or hetero subunits. The N-terminal extracellular regions of the subunits make up the ligand-binding domain (LBD), with two or five binding sites in hetero and homo pentamers, respectively. The central regions form the transmembrane domain (TMD), which is an ion channel selective for cations such as Na ϩ , K ϩ , and Ca 2ϩ [supporting information (SI) Fig. S1]. A central issue is the mechanisms of channel activation by agonists and inhibition by antagonists. How is agonist/ antagonist binding transmitted to trigger channel opening/ closing? What are the necessary conformational changes? Experimental and computational studies together have begun to provide mechanistic insights at the atomic level. Here, we present a molecular dynamics (MD) simulation study of the ␣7 nAChR LBD (consisting of five ␣-type subunits), both in apo form and in ␣-Cobratoxin-bound form. Our simulation results are in broad agreement with a wealth of experimental data. Combining the present work with experimental data and previous computational results, we propose a mechanistic model in which the apo form, although predominantly sampling the ''closed'' state, can make excursions into the ''open'' state. Details of the conformational change leading to channel activation/inhibition are presented.A number ...

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Section: Resultssupporting

confidence: 73%

mentioning

confidence: 84%

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Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Tjong

Zhou

2008

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

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“…Inspection of homology models of the ␣7 subunit (24,25), and of the 4Å resolution structure of the Torpedo nAChR from which they were derived (26,27), reveals an intrasubunit cavity between the four transmembrane ␣-helices (Fig. S4).…”

Section: Molecular Docking Simulationsmentioning

confidence: 99%

“…Computational docking simulations (28) were performed with three previously described ␣7 subunit homology models (24,25,29). Our aim was to examine whether this intrasubunit cavity is a plausible binding site for nAChR potentiators and where within the ␣7 homology model PNU-120596 and LY-2087101 would be predicted to bind.…”

Section: Molecular Docking Simulationsmentioning

confidence: 99%

Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

Young

Zwart

Walker

et al. 2008

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

225

320

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Positive allosteric modulators of ␣7 nicotinic acetylcholine receptors (nAChRs) have attracted considerable interest as potential tools for the treatment of neurological and psychiatric disorders such as Alzheimer's disease and schizophrenia. However, despite the potential therapeutic usefulness of these compounds, little is known about their mechanism of action. Here, we have examined two allosteric potentiators of ␣7 nAChRs (PNU-120596 and LY-2087101). From studies with a series of subunit chimeras, we have identified the transmembrane regions of ␣7 as being critical in facilitating potentiation of agonist-evoked responses. Furthermore, we have identified five transmembrane amino acids that, when mutated, significantly reduce potentiation of ␣7 nAChRs. The amino acids we have identified are located within the ␣-helical transmembrane domains TM1 (S222 and A225), TM2 (M253), and TM4 (F455 and C459). Mutation of either A225 or M253 individually have particularly profound effects, reducing potentiation of EC 20 concentrations of acetylcholine to a tenth of the level seen with wild-type ␣7. Reference to homology models of the ␣7 nAChR, based on the 4Å structure of the Torpedo nAChR, indicates that the side chains of all five amino acids point toward an intrasubunit cavity located between the four ␣-helical transmembrane domains. Computer docking simulations predict that the allosteric compounds such as PNU-120596 and LY-2087101 may bind within this intrasubunit cavity, much as neurosteroids and volatile anesthetics are thought to interact with GABA A and glycine receptors. Our findings suggest that this is a conserved modulatory allosteric site within neurotransmitter-gated ion channels.allosteric modulators ͉ neurotransmitter receptor N icotinic acetylcholine receptors (nAChRs) are excitatory neurotransmitter-gated ion channels and members of a superfamily that also includes ionotropic receptors for 5-hydroxytryptamine (5-HT; serotonin), glycine and ␥-aminobutyric acid (GABA) (1, 2). Nicotinic receptors are allosteric proteins (3), which have been implicated in a variety of neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, and schizophrenia (4-6). As a consequence, nAChRs are viewed as being important targets for therapeutic drug discovery (7,8).Although most nAChR subunits assemble only into heteromeric nAChRs (9, 10), the ␣7 and ␣8 subunits are important exceptions. Both ␣7 and ␣8 are able to generate functional homomeric nAChRs (11, 12) and have much closer sequence similarity to each other than to other nAChR subunits (2, 9). Whereas there is evidence that ␣7 nAChRs are an important receptor subtype in the mammalian brain (and in other vertebrates), the ␣8 subunit has been identified only in avian species. The 5-HT receptor 3A subunit (5-HT 3A ) has close sequence similarity to nAChR subunits (2) and, like the nAChR ␣7 and ␣8 subunits, is able to generate functional homomeric cationselective ion channels (13). Indeed, the ability of ␣7 and 5-HT 3A subunits to...

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Ion Channels: Computational Analysis

Kurnikova

2008

Wiley Encyclopedia of Chemical Biology

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Ion channels are proteins that are embedded in the lipid bilayer and open water filled pores for ion conduction. This article briefly discusses applications of the methods of computational chemistry to model structure and properties of ion channels. Molecular dynamics simulations are applied to study structure–function relationships in ion channels, their interaction with the lipid bilayer, as well as some aspects of gating and selectivity. Ion permeation properties of the channels are typically modeled using coarse‐grained theories based on continuum representation of water, protein and sometimes permeating ions. In such models, interaction of ions with the environment is governed by the Poisson equation of classic electrostatics. Dynamic flow of ions is modeled by using either Brownian Dynamics (BD) [or alternatively Dynamic Monte Carlo methods (DMC)] or by using continuum diffusion formalism. A model that combines continuum diffusion formalism with the Poisson equation is termed Poisson–Nernst–Planck (PNP) theory. A generalized continuum flow theory that accounts for a single ion interaction with the environment is termed Potential of Mean Force PMP (PMFPNP). The main limitation of both BD and PNP theories stems from the rigid representation of the protein and the membrane. In many hybrid models, this limitation has been overcome.

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Channel Opening Motion of α7 Nicotinic Acetylcholine Receptor as Suggested by Normal Mode Analysis

Cited by 106 publications

References 60 publications

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

Ion Channels: Computational Analysis

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