Structure and gating mechanism of the α7 nicotinic acetylcholine receptor

Noviello, Colleen; Gharpure, Anant; Mukhtasimova, Nuriya; Cabuco, Rico; Baxter, L.; Borek, Dominika; Sine, Steven M.; Hibbs, Ryan

doi:10.1016/j.cell.2021.02.049

Cited by 194 publications

(286 citation statements)

References 109 publications

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“…When this manuscript is in preparation, Noviello et al reported cryo-EM structures of human α7 in antagonist (α-bungarotoxin, α-bgt)-bound closed state, agonist (Epibatidine)-bound desensitized state and agonist (Epibatidine)/PAM (PNU)-bound activated state. 11 The overall structures of apo and α-bgt-bound α7 are almost the same (Supplementary information, Fig. S 5c ).…”

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confidence: 86%

“…Notably, despite including a high concentration of PNU in the cryo-EM sample, PNU molecules were not confidently positioned in the Epibatidine/PNU-bound α7 structure reported by Noviello et al It was suspected that the locally dynamic nature of the TMD in the activated state, which correlates with its lower local resolution, precludes visualization of the small molecules. 11 …”

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confidence: 99%

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Structural basis of human α7 nicotinic acetylcholine receptor activation

et al. 2021

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confidence: 86%

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confidence: 99%

Structural basis of human α7 nicotinic acetylcholine receptor activation

et al. 2021

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“…While the application of a variety of experimental and computational approaches together with the experimental structures available (e.g., [63][64][65]67]) have led to a greater insight into the function of nAChR, the structural changes induced by agonist binding/unbinding and how those changes are propagated to the ion channel remain poorly understood. Answering this question requires an approach that allows us to follow the receptor's time-dependent response as its conformation adapts to the agonist binding or unbinding.…”

Section: Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems

et al. 2021

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A dynamical approach to nonequilibrium molecular dynamics (D-NEMD), proposed in the 1970s by Ciccotti et al., is undergoing a renaissance and is having increasing impact in the study of biological macromolecules. This D-NEMD approach, combining MD simulations in stationary (in particular, equilibrium) and nonequilibrium conditions, allows for the determination of the time-dependent structural response of a system using the Kubo–Onsager relation. Besides providing a detailed picture of the system’s dynamic structural response to an external perturbation, this approach also has the advantage that the statistical significance of the response can be assessed. The D-NEMD approach has been used recently to identify a general mechanism of inter-domain signal propagation in nicotinic acetylcholine receptors, and allosteric effects in $$\upbeta $$ β -lactamase enzymes, for example. It complements equilibrium MD and is a very promising approach to identifying and analysing allosteric effects. Here, we review the D-NEMD approach and its application to biomolecular systems, including transporters, receptors, and enzymes. Graphic abstract

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“…High resolution structures have now been obtained for several members of the cys-loop family including the muscle nAChR ( Figure 1 C) [ 10 , 11 , 12 ] neuronal α4β2, α3β4, and α7 nAChRs [ 13 , 14 , 15 ], GABA A receptor [ 16 ], glycine α3 receptor [ 17 ], and 5HT 3 receptor [ 18 ]. These reveal a conserved architecture of the channel and constituent subunits [ 19 , 20 ], as well as providing new insights into the structural basis of transmitter binding and channel gating.…”

Section: Structure Of the Nachr Intracellular Domainmentioning

confidence: 99%

An Inside Job: Molecular Determinants for Postsynaptic Localization of Nicotinic Acetylcholine Receptors

Ferns

2021

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Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission at neuromuscular and autonomic ganglionic synapses in the peripheral nervous system. The postsynaptic localization of muscle ((α1)2β1γδ) and neuronal ((α3β4)2β4) nicotinic receptors at these synapses is mediated by interactions between the nAChR intracellular domains and cytoplasmic scaffolding proteins. Recent high resolution structures and functional studies provide new insights into the molecular determinants that mediate these interactions. Surprisingly, they reveal that the muscle nAChR binds 1–3 rapsyn scaffolding molecules, which dimerize and thereby form an interconnected lattice between receptors. Moreover, rapsyn binds two distinct sites on the nAChR subunit cytoplasmic loops; the MA-helix on one or more subunits and a motif specific to the β subunit. Binding at the latter site is regulated by agrin-induced phosphorylation of βY390, and increases the stoichiometry of rapsyn/AChR complexes. Similarly, the neuronal nAChR may be localized at ganglionic synapses by phosphorylation-dependent interactions with 14-3-3 adaptor proteins which bind specific motifs in each of the α3 subunit cytoplasmic loops. Thus, postsynaptic localization of nAChRs is mediated by regulated interactions with multiple scaffolding molecules, and the stoichiometry of these complexes likely helps regulate the number, density, and stability of receptors at the synapse.

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Structure and gating mechanism of the α7 nicotinic acetylcholine receptor

Cited by 194 publications

References 109 publications

Structural basis of human α7 nicotinic acetylcholine receptor activation

Structural basis of human α7 nicotinic acetylcholine receptor activation

Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems

An Inside Job: Molecular Determinants for Postsynaptic Localization of Nicotinic Acetylcholine Receptors

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