Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations.

Jierong Wen,David J Adams,Andrew Hung

doi:10.3390/md18070349

Abstract

Notably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)2(β2)3 nAChR subunit arrangement comprises a pair of α3(+)β2(−) and β2(+)α3(−) interfaces, and a β2(+)β2(−) interface. The β2(+)β2(−) interface has been suggested to have higher agonist affinity relative to the α3(+)β2(−) and β2(+)α3(−) interfaces. Nevertheless, the interactions formed by these subunit interfaces with α-conotoxins are not well understood. Therefore, in order to address this, we modelled the interactions between α-conotoxin LsIA and the α3β2 subtype. The results suggest that the C-terminal carboxylation of LsIA predominantly influenced the enhanced contacts of the conotoxin via residues P7, P14 and C17 on LsIA at the α3(+)β2(−) and β2(+)α3(−) interfaces. However, this enhancement is subtle at the β2(+)β2(−) site, which can compensate the augmented interactions by LsIA at α3(+)β2(−) and β2(+)α3(−) binding sites. Therefore, the divergent interactions at the individual binding interface may account for the minor changes in binding affinity to α3β2 subtype by C-terminal carboxylation of LsIA versus its wild type, as shown in previous experimental results. Overall, these findings may facilitate the development of new drug leads or subtype-selective probes.

Highlights

Neuronal nicotinic acetylcholine receptors are ligand-gated ion channels [1] that play important roles in the mediating signalling transmission between neurons
The root-mean-square deviation (RMSD) time series plots for the LsIA- and LsIA#-α3β2 complexes are shown in Figure 2A–D, each time series of which was taken as an average over 28 independent simulations
The fitting was performed on the Cα atoms of the entire receptor-ligand complex and RMSD values were calculated for the respective individual chains, discussed below

Summary

Introduction

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels [1] that play important roles in the mediating signalling transmission between neurons They are related to numerous neurological disorders and diseases, such as Parkinson’s disease, Alzheimer’s disease, dementia, schizophrenia and addiction [2,3,4]. The ECD is of particular importance due to the presence of the canonical ligand-binding domain (LBD) at the interface of two adjacent subunits [6,7]. It has been demonstrated that the α subunit ECD can facilitate the binding of agonists [8], such as acetylcholine (ACh), at the LBD [1], resulting in the opening of the channel in the TMD

Methods

Results

Discussion

Conclusion