Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor

Tabassum, Nargis; Ma, Qianyun; Wu, Guanzhao; Jiang, Tao; Yu, Rilei

doi:10.1007/s00894-017-3419-4

Cited by 4 publications

(2 citation statements)

References 25 publications

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“…A proposed paradigm of antagonism compared to agonism of nAChRs is that agonists stabilise the C‐loop into a relatively closed conformation whereas antagonist binding results in a larger opening of the C‐loop (Tabassum, Ma, Wu, Jiang, & Yu, ). In our simulations, the C‐loop of the α4β2 nAChR/DHβE displayed an open conformation similar to that of the crystal structure of the complex between AChBP and DHβE (Shahsavar et al, ).…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Tae

et al. 2019

British J Pharmacology

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Background and Purpose: The heteromeric α4β2 nicotinic acetylcholine receptor (nAChR) is abundant in the human brain and is associated with a range of CNS disorders. This nAChR subtype has been recently crystallised in a conformation that was proposed to represent a desensitised state. Here, we investigated the conformational transition mechanism of this nAChR from a desensitised to a closed/resting state.Experimental Approach: The competitive antagonist dihydro-β-erythroidine (DHβE) was modelled by replacement of the agonist nicotine in the α4β2 nAChR experimental structure. DHβE is used both in vitro and in vivo for its ability to block α4β2 nAChRs. This system was studied by three molecular dynamics simulations with a combined simulation time of 2.6 μs. Electrophysiological studies of mutated receptors were performed to validate the simulation results. Key Results: The relative positions of the extracellular and transmembrane domains in the models are distinct from those of the desensitised state structure and are compatible with experimental structures of Cys-loop receptors captured in a closed/resting state.Conclusions and Implications: Our model suggests that the side chains of α4 L257 (9′) and α4 L264 (16′) are the main constrictions in the transmembrane pore. The involvement of position 9′ in channel gating is well established, but position 16′ was only previously identified as a gate for the bacterial channels, ELIC and GLIC. L257 but not L264 was found to influence the slow component of desensitisation.The structure of the antagonist-bound state proposed here should be valuable for the development of therapeutic or insecticide compounds.

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Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Tae

et al. 2019

British J Pharmacology

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“…Structural studies have confirmed that ligands with different efficacies on nAChRs also induce different conformations of AChBP. 26–28 In the Concentration Response Curves (CRC's) tubocurarine (antagonist) shows a smaller ΔSHG than the other compounds, confirming that the SHG assay was able to distinguish conformational changes induced by these compounds in an AChBP conjugate labelled on K158. The experiment also indicated that the probe's location in the orthosteric site did not block the binding of these well-studied ligands.…”

Section: Resultsmentioning

confidence: 71%