From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR

Bo Lin, Manyu Xu, Xiaopeng Zhu, Yong Wu, Xi Liu, Dongting Zhangsun, Yuanyan Hu, Shi-Hua Xiang, Igor E. Kasheverov, Victor I. Tsetlin, Xinquan Wang, Sulan Luo

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Abstract

Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of AChBP in complex with α-conotoxins provide important insights into the interactions of α-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why α-conotoxin GIC is strongly selective for α3β2 nAChR, this question has not yet been solved. Here we present the structure of α-conotoxin GIC in complex with Aplysia californica AChBP (Ac-AChBP) at a resolution of 2.1 Å. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human α3β2 vs α3β4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and α3β2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and α3β2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes.

Original languageEnglish (US)
Article number22349
JournalScientific Reports
Volume6
DOIs
StatePublished - Mar 1 2016

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Conotoxins
Aplysia
Acetylcholine
Carrier Proteins
Nicotinic Receptors
X-Rays
Electrophysiology
Pharmacology
Ligands

ASJC Scopus subject areas

  • General

Cite this

From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR. / Lin, Bo; Xu, Manyu; Zhu, Xiaopeng; Wu, Yong; Liu, Xi; Zhangsun, Dongting; Hu, Yuanyan; Xiang, Shi-Hua; Kasheverov, Igor E.; Tsetlin, Victor I.; Wang, Xinquan; Luo, Sulan.

In: Scientific Reports, Vol. 6, 22349, 01.03.2016.

Research output: Contribution to journalArticle

Lin, Bo ; Xu, Manyu ; Zhu, Xiaopeng ; Wu, Yong ; Liu, Xi ; Zhangsun, Dongting ; Hu, Yuanyan ; Xiang, Shi-Hua ; Kasheverov, Igor E. ; Tsetlin, Victor I. ; Wang, Xinquan ; Luo, Sulan. / From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR. In: Scientific Reports. 2016 ; Vol. 6.
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abstract = "Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of AChBP in complex with α-conotoxins provide important insights into the interactions of α-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why α-conotoxin GIC is strongly selective for α3β2 nAChR, this question has not yet been solved. Here we present the structure of α-conotoxin GIC in complex with Aplysia californica AChBP (Ac-AChBP) at a resolution of 2.1 {\AA}. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human α3β2 vs α3β4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and α3β2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and α3β2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes.",
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