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Conotoxin αd-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors

Journal Article


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Abstract


  • Nicotinic acetylcholine receptors (nAChRs) play essential roles in transmitting acetylcholine-mediated neural signals across synapses and neuromuscular junctions, and are also closely linked to various diseases and clinical conditions. Therefore, novel nAChR-specific compounds have great potential for both neuroscience research and clinical applications. Conotoxins, the peptide neurotoxins produced by cone snails, are a rich reservoir of novel ligands that target receptors, ion channels and transporters in the nervous system. From the venom of Conus generalis, we identified a novel dimeric nAChR-inhibiting αD-conotoxin GeXXA. By solving the crystal structure and performing structure-guided dissection of this toxin, we demonstrated that the monomeric C-terminal domain of αD-GeXXA, GeXXA-CTD, retains inhibitory activity against the α9α10 nAChR subtype. Furthermore, we identified that His7 of the rat α10 nAChR subunit determines the species preference of αD-GeXXA, and is probably part of the binding site of this toxin. These results together suggest that αD-GeXXA cooperatively binds to two inter-subunit interfaces on the top surface of nAChR, thus allosterically disturbing the opening of the receptor. The novel antagonistic mechanism of αD-GeXXA via a new binding site on nAChRs provides a valuable basis for the rational design of new nAChR-targeting compounds.

Authors


  •   Xu, Shaoqiong (external author)
  •   Zhang, Tianlong (external author)
  •   Kompella, Shiva N. (external author)
  •   Yan, Mengdi (external author)
  •   Lu, Aiping (external author)
  •   Wang, Yanfang (external author)
  •   Shao, Xiaoxia (external author)
  •   Chi, Chengwu (external author)
  •   Adams, David J.
  •   Ding, Jianping (external author)
  •   Wang, Chunguang (external author)

Publication Date


  • 2015

Citation


  • Xu, S., Zhang, T., Kompella, S. N., Yan, M., Lu, A., Wang, Y., Shao, X., Chi, C., Adams, D. J., Ding, J. & Wang, C. (2015). Conotoxin αd-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors. Scientific Reports, 5 14261-1-14261-8.

Scopus Eid


  • 2-s2.0-84942279410

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1603&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/581

Start Page


  • 14261-1

End Page


  • 14261-8

Volume


  • 5

Abstract


  • Nicotinic acetylcholine receptors (nAChRs) play essential roles in transmitting acetylcholine-mediated neural signals across synapses and neuromuscular junctions, and are also closely linked to various diseases and clinical conditions. Therefore, novel nAChR-specific compounds have great potential for both neuroscience research and clinical applications. Conotoxins, the peptide neurotoxins produced by cone snails, are a rich reservoir of novel ligands that target receptors, ion channels and transporters in the nervous system. From the venom of Conus generalis, we identified a novel dimeric nAChR-inhibiting αD-conotoxin GeXXA. By solving the crystal structure and performing structure-guided dissection of this toxin, we demonstrated that the monomeric C-terminal domain of αD-GeXXA, GeXXA-CTD, retains inhibitory activity against the α9α10 nAChR subtype. Furthermore, we identified that His7 of the rat α10 nAChR subunit determines the species preference of αD-GeXXA, and is probably part of the binding site of this toxin. These results together suggest that αD-GeXXA cooperatively binds to two inter-subunit interfaces on the top surface of nAChR, thus allosterically disturbing the opening of the receptor. The novel antagonistic mechanism of αD-GeXXA via a new binding site on nAChRs provides a valuable basis for the rational design of new nAChR-targeting compounds.

Authors


  •   Xu, Shaoqiong (external author)
  •   Zhang, Tianlong (external author)
  •   Kompella, Shiva N. (external author)
  •   Yan, Mengdi (external author)
  •   Lu, Aiping (external author)
  •   Wang, Yanfang (external author)
  •   Shao, Xiaoxia (external author)
  •   Chi, Chengwu (external author)
  •   Adams, David J.
  •   Ding, Jianping (external author)
  •   Wang, Chunguang (external author)

Publication Date


  • 2015

Citation


  • Xu, S., Zhang, T., Kompella, S. N., Yan, M., Lu, A., Wang, Y., Shao, X., Chi, C., Adams, D. J., Ding, J. & Wang, C. (2015). Conotoxin αd-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors. Scientific Reports, 5 14261-1-14261-8.

Scopus Eid


  • 2-s2.0-84942279410

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1603&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/581

Start Page


  • 14261-1

End Page


  • 14261-8

Volume


  • 5