title: Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes.
abstract: T-superfamily conotoxins have a typical cysteine pattern of "CC-CC", and are known to mainly target calcium or sodium ion channels. Recently, we screened the targets of a series of T-superfamily conotoxins and found that a new T-superfamily conotoxin TxVC (KPCCSIHDNSCCGL-NH2) from the venom of Conus textile. It selectively targeted the neuronal nicotinic acetylcholine receptor (nAChR) subtypes α4β2 and α3β2, with IC50 values of 343.4 and 1047.2nM, respectively, but did not exhibit obvious pharmacological effects on voltage-gated potassium, sodium or calcium channel in DRG cells, the BK channels expressed in HEK293 cells, or the Kv channels in LβT2 cells. The changes in the inhibitory activities of its Ala mutants, the NMR structure, and molecular simulation results based on other conotoxins targeting nAChR α4β2, all demonstrated that the residues Ile(6) and Leu(14) were the main hydrophobic pharmacophores. To our best knowledge, this is the first T-superfamily conotoxin that inhibits neuronal nAChRs and possesses high binding affinity to α4β2. This finding will expand the knowledge of the targets of T-superfamily conotoxins and the motif information could help the design of new nAChR inhibitors.
authors.affiliation: Beijing Institute of Biotechnology, Beijing 10071, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Science, Wuhan 430071, China.
authors.forename: Tianpeng
authors.initials: T
authors.lastname: Du
authors.affiliation: Beijing Institute of Biotechnology, Beijing 10071, China.
authors.forename: Zhuguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ding
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Science, Wuhan 430071, China. Electronic address: lingjiang@wipm.ac.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Beijing Institute of Biotechnology, Beijing 10071, China. Electronic address: qy_dai@yahoo.com.
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Dai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D020916:Conotoxins / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D052078:Conus Snail / Q000737:chemistry* / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014981:Xenopus
chemical_list: D020916:Conotoxins; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C419362:nicotinic receptor alpha3beta2; C403531:nicotinic receptor alpha4beta2
keywords: Conus textile; NMR structure; Neuronal nicotinic acetylcholine receptor; Selectivity; T-superfamily conotoxin TxVC