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Mar. Drugs 2018, 16(4), 112; https://doi.org/10.3390/md16040112

Cloning, Synthesis and Functional Characterization of a Novel α-Conotoxin Lt1.3

1
Beijing Institute of Biotechnology, Beijing 100071, China
2
Institute of Physical Science and Information Technology, Anhui University, Hefei 236041, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 20 February 2018 / Revised: 16 March 2018 / Accepted: 22 March 2018 / Published: 31 March 2018
(This article belongs to the Special Issue Marine Invertebrate Toxins)
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Abstract

α-Conotoxins (α-CTxs) are small peptides composed of 11 to 20 amino acid residues with two disulfide bridges. Most of them potently and selectively target nicotinic acetylcholine receptor (nAChR) subtypes, and a few were found to inhibit the GABAB receptor (GABABR)-coupled N-type calcium channels (Cav2.2). However, in all of α-CTxs targeting both receptors, the disulfide connectivity arrangement “C1-C3, C2-C4” is present. In this work, a novel α4/7-CTx named Lt1.3 (GCCSHPACSGNNPYFC-NH2) was cloned from the venom ducts of Conus litteratus (C. litteratus) in the South China Sea. Lt1.3 was then chemically synthesized and two isomers with disulfide bridges “C1-C3, C2-C4” and “C1-C4, C2-C3” were found and functionally characterized. Electrophysiological experiments showed that Lt1.3 containing the common disulfide bridges “C1-C3, C2-C4” potently and selectively inhibited α3β2 nAChRs and not GABABR-coupled Cav2.2. Surprisingly, but the isomer with the disulfide bridges “C1-C4, C2-C3” showed exactly the opposite inhibitory activity, inhibiting only GABABR-coupled Cav2.2 and not α3β2 nAChRs. These findings expand the knowledge of the targets and selectivity of α-CTxs and provide a new structural motif to inhibit the GABABR-coupled Cav2.2. View Full-Text
Keywords: α-conotoxins; Lt1.3; cloning; synthesis; α3β2 nAChRs; GABABR-coupled Cav2.2 α-conotoxins; Lt1.3; cloning; synthesis; α3β2 nAChRs; GABABR-coupled Cav2.2
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Chen, J.; Liang, L.; Ning, H.; Cai, F.; Liu, Z.; Zhang, L.; Zhou, L.; Dai, Q. Cloning, Synthesis and Functional Characterization of a Novel α-Conotoxin Lt1.3. Mar. Drugs 2018, 16, 112.

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