Abstract
The α3* nAChRs, which are considered to be promising drug targets for problems such as pain, addiction, cardiovascular function, cognitive disorders etc., are found throughout the central and peripheral nervous system. The α-conotoxin (α-CTx) LvIA has been identified as the most selective inhibitor of α3β2 nAChRs known to date, and it can distinguish the α3β2 nAChR subtype from the α6/α3β2β3 and α3β4 nAChR subtypes. However, the mechanism of its selectivity towards α3β2, α6/α3β2β3, and α3β4 nAChRs remains elusive. Here we report the co-crystal structure of LvIA in complex with Aplysia californica acetylcholine binding protein (Ac-AChBP) at a resolution of 3.4 Å. Based on the structure of this complex, together with homology modeling based on other nAChR subtypes and binding affinity assays, we conclude that Asp-11 of LvIA plays an important role in the selectivity of LvIA towards α3β2 and α3/α6β2β3 nAChRs by making a salt bridge with Lys-155 of the rat α3 subunit. Asn-9 lies within a hydrophobic pocket that is formed by Met-36, Thr-59, and Phe-119 of the rat β2 subunit in the α3β2 nAChR model, revealing the reason for its more potent selectivity towards the α3β2 nAChR subtype. These results provide molecular insights that can be used to design ligands that selectively target α3β2 nAChRs, with significant implications for the design of new therapeutic α-CTxs.
Highlights
Neuronal nicotinic acetylcholine receptors are a group of ligand-gated cation-selective ion channels that play key roles in fast signal transmission in the nervous system (Zoli et al, 2015; Hurst et al, 2013)
To reveal the mechanism responsible for the distinctive binding profile and selectivity of LvIA towards different α3*nicotinic acetylcholine receptors (nAChRs), we solved the crystal structure of α-conotoxin LvIA in complex with the acetylcholine binding protein from Aplysia californica (Ac-acetylcholine-binding proteins (AChBPs)) at 3.4 Å resolution. Based on this complex structure, together with homology models based on other nAChR subtypes, as well as binding affinity assays, we offer an explanation for its binding features, which has significant implications for the design of new therapeutic α-conotoxin derivatives
Analysis of the precise role of α3* nAChRs has been hampered by the lack of specific molecular probes
Summary
Neuronal nicotinic acetylcholine receptors (nAChRs) are a group of ligand-gated cation-selective ion channels that play key roles in fast signal transmission in the nervous system (Zoli et al, 2015; Hurst et al, 2013). As one of the largest and most diverse groups of nAChR antagonists, they have tremendous therapeutic potential for the treatment of various neurological diseases, including epilepsy and neuropathic pain (Tsetlin et al, 2009; Azam and McIntosh, 2009) Owing to their relatively rigid framework structure, combined with great diversity at the amino-acid sequence level, α-conotoxins bind to distinct nAChR subtypes with different selectivity (Rucktooa et al, 2009), which makes them remarkable probes for structural studies. To reveal the mechanism responsible for the distinctive binding profile and selectivity of LvIA towards different α3*nAChRs, we solved the crystal structure of α-conotoxin LvIA in complex with the acetylcholine binding protein from Aplysia californica (Ac-AChBP) at 3.4 Å resolution Based on this complex structure, together with homology models based on other nAChR subtypes, as well as binding affinity assays, we offer an explanation for its binding features, which has significant implications for the design of new therapeutic α-conotoxin derivatives
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