4X9Z

Dimeric conotoxin alphaD-GeXXA

Summary for 4X9Z

• Entry DOI: 10.2210/pdb4x9z/pdb
• Descriptor: alphaD-conotoxin GeXXA from the venom of Conus generalis (2 entities in total)
• Functional Keywords: alpha-conotoxin, gexxa, nicotinic acetylcholine receptor, homodimer, toxin
• Biological source: Conus generalis
• Total number of polymer chains: 2
• Total formula weight: 11289.45

Authors

Xu, S.,Zhang, T.,Kompella, S.,Adams, D.,Ding, J.,Wang, C. (deposition date: 2014-12-12, release date: 2015-12-02, Last modification date: 2024-11-06)

Primary 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.
Conotoxin alpha D-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors
Sci Rep, 5:14261-14261, 2015

PubMed 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.

PubMed: 26395518
DOI: 10.1038/srep14261

Experimental method

X-RAY DIFFRACTION (1.5 Å)