4x9z
Dimeric conotoxin alphaD-GeXXADimeric conotoxin alphaD-GeXXA
Structural highlights
FunctionCDKA_CONGR Alpha-D-conopeptides act as non-competitive inhibitors of nicotinic acetylcholine receptors (nAChR). Through its two C-terminal domains, this homodimeric protein would bind to two nAChR allosteric sites, located outside the nAChR C-loop of the principal binding face and at the adjacent binding interface in a clockwise direction (By similarity). This toxin has strong inhibitory activity on rat alpha-9-alpha-10 (CHRNA9-CHRNA10) (IC(50)=1.2 nM) and a moderate inhibitory activity on human alpha-7 (CHRNA7) (IC(50)=210 nM), rat alpha-3-beta-2 (CHRNA3-CHRNB2) (IC(50)=498 nM), rat alpha-3-beta-4 (CHRNA3-CHRNB4) (IC(50)=614 nM) and rat alpha-1-beta-1-delta-epsilon (CHRNA1-CHRNB1-CHRNE-CHRND) (IC(50)=743 nM) subtypes (PubMed:26395518). Shows a weaker inhibitory activity on human alpha-9-alpha-10 (IC(50)=28 nM) than on the rat channel (PubMed:26395518). This is explained by a different residue in the probable binding site (His-31 in rat alpha-10 and Leu-31 in human) (PubMed:26395518).[UniProtKB:P0C1W6][1] Publication Abstract from PubMedNicotinic 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 alphaD-conotoxin GeXXA. By solving the crystal structure and performing structure-guided dissection of this toxin, we demonstrated that the monomeric C-terminal domain of alphaD-GeXXA, GeXXA-CTD, retains inhibitory activity against the alpha9alpha10 nAChR subtype. Furthermore, we identified that His7 of the rat alpha10 nAChR subunit determines the species preference of alphaD-GeXXA, and is probably part of the binding site of this toxin. These results together suggest that alphaD-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 alphaD-GeXXA via a new binding site on nAChRs provides a valuable basis for the rational design of new nAChR-targeting compounds. Conotoxin alphaD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors.,Xu S, Zhang T, Kompella SN, Yan M, Lu A, Wang Y, Shao X, Chi C, Adams DJ, Ding J, Wang C Sci Rep. 2015 Sep 23;5:14261. doi: 10.1038/srep14261. PMID:26395518[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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