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

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.

journal_name

Mar Drugs

journal_title

Marine drugs

authors

Wen J,Adams DJ,Hung A

doi

10.3390/md18070349

subject

Has Abstract

pub_date

2020-07-03 00:00:00

issue

7

issn

1660-3397

pii

md18070349

journal_volume

18

pub_type

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