Characterization of a Novel α‑Conotoxin TxID from Conus textile That Potently Blocks Rat α3β4 Nicotinic Acetylcholine Receptors
The α3β4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an α-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthet...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-12, Vol.56 (23), p.9655-9663 |
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| container_issue | 23 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 56 |
| creator | Luo, Sulan Zhangsun, Dongting Zhu, Xiaopeng Wu, Yong Hu, Yuanyan Christensen, Sean Harvey, Peta J Akcan, Muharrem Craik, David J McIntosh, J. Michael |
| description | The α3β4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an α-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxID blocked rat α3β4 nAChRs with a 12.5 nM IC50, which places it among the most potent α3β4 nAChR antagonists. TxID also blocked the closely related α6/α3β4 with a 94 nM IC50 but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular α-CTx fold but with different surface charge distribution to other 4/6 family members. α-CTx TxID is a novel tool with which to probe the structure and function of α3β4 nAChRs. |
| doi_str_mv | 10.1021/jm401254c |
| format | Article |
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Michael</creator><creatorcontrib>Luo, Sulan ; Zhangsun, Dongting ; Zhu, Xiaopeng ; Wu, Yong ; Hu, Yuanyan ; Christensen, Sean ; Harvey, Peta J ; Akcan, Muharrem ; Craik, David J ; McIntosh, J. Michael</creatorcontrib><description>The α3β4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an α-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxID blocked rat α3β4 nAChRs with a 12.5 nM IC50, which places it among the most potent α3β4 nAChR antagonists. TxID also blocked the closely related α6/α3β4 with a 94 nM IC50 but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular α-CTx fold but with different surface charge distribution to other 4/6 family members. α-CTx TxID is a novel tool with which to probe the structure and function of α3β4 nAChRs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm401254c</identifier><identifier>PMID: 24200193</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Conotoxins - chemistry ; Conotoxins - pharmacology ; Conus Snail ; Inhibitory Concentration 50 ; Nicotinic Antagonists - chemistry ; Nicotinic Antagonists - pharmacology ; Oocytes - metabolism ; Rats ; Receptors, Nicotinic - drug effects ; Xenopus laevis</subject><ispartof>Journal of medicinal chemistry, 2013-12, Vol.56 (23), p.9655-9663</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a350t-36f0ed6a42c7972b4668e3a825c005462045ed649db0f6dd0159ca478480ae513</citedby><cites>FETCH-LOGICAL-a350t-36f0ed6a42c7972b4668e3a825c005462045ed649db0f6dd0159ca478480ae513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm401254c$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm401254c$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24200193$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luo, Sulan</creatorcontrib><creatorcontrib>Zhangsun, Dongting</creatorcontrib><creatorcontrib>Zhu, Xiaopeng</creatorcontrib><creatorcontrib>Wu, Yong</creatorcontrib><creatorcontrib>Hu, Yuanyan</creatorcontrib><creatorcontrib>Christensen, Sean</creatorcontrib><creatorcontrib>Harvey, Peta J</creatorcontrib><creatorcontrib>Akcan, Muharrem</creatorcontrib><creatorcontrib>Craik, David J</creatorcontrib><creatorcontrib>McIntosh, J. Michael</creatorcontrib><title>Characterization of a Novel α‑Conotoxin TxID from Conus textile That Potently Blocks Rat α3β4 Nicotinic Acetylcholine Receptors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The α3β4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an α-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxID blocked rat α3β4 nAChRs with a 12.5 nM IC50, which places it among the most potent α3β4 nAChR antagonists. TxID also blocked the closely related α6/α3β4 with a 94 nM IC50 but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular α-CTx fold but with different surface charge distribution to other 4/6 family members. α-CTx TxID is a novel tool with which to probe the structure and function of α3β4 nAChRs.</description><subject>Animals</subject><subject>Conotoxins - chemistry</subject><subject>Conotoxins - pharmacology</subject><subject>Conus Snail</subject><subject>Inhibitory Concentration 50</subject><subject>Nicotinic Antagonists - chemistry</subject><subject>Nicotinic Antagonists - pharmacology</subject><subject>Oocytes - metabolism</subject><subject>Rats</subject><subject>Receptors, Nicotinic - drug effects</subject><subject>Xenopus laevis</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtOwzAURS0EoqUwYAPIEwYMAs-fpMkQwq9SVVBVxpHrOKpLEle2i1pGDNgASykL6SJYCUGFjhg96b6jq6uD0DGBcwKUXEwrDoSGXO6gNgkpBDwGvovaAJQGNKKshQ6cmwIAI5TtoxblFIAkrI3e04mwQnpl9avw2tTYFFjggXlRJV6vvt4-UlMbbxa6xqNF7xoX1lS4yeYOe7XwulR4NBEePxqval8u8VVp5LPDwyZbr9j6k-OBlsbrWkt8KZVflnJiSl0rPFRSzbyx7hDtFaJ06uj3dtDT7c0ovQ_6D3e99LIfCBaCD1hUgMojwansJl065lEUKyZiGkqAkEcUeNj8eZKPoYjyHEiYSMG7caNDqJCwDjrb9EprnLOqyGZWV8IuMwLZj8lsa7JhTzbsbD6uVL4l_9Q1wOkGENJlUzO3dTP9n6JvzRl91Q</recordid><startdate>20131212</startdate><enddate>20131212</enddate><creator>Luo, Sulan</creator><creator>Zhangsun, Dongting</creator><creator>Zhu, Xiaopeng</creator><creator>Wu, Yong</creator><creator>Hu, Yuanyan</creator><creator>Christensen, Sean</creator><creator>Harvey, Peta J</creator><creator>Akcan, Muharrem</creator><creator>Craik, David J</creator><creator>McIntosh, J. Michael</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20131212</creationdate><title>Characterization of a Novel α‑Conotoxin TxID from Conus textile That Potently Blocks Rat α3β4 Nicotinic Acetylcholine Receptors</title><author>Luo, Sulan ; Zhangsun, Dongting ; Zhu, Xiaopeng ; Wu, Yong ; Hu, Yuanyan ; Christensen, Sean ; Harvey, Peta J ; Akcan, Muharrem ; Craik, David J ; McIntosh, J. Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a350t-36f0ed6a42c7972b4668e3a825c005462045ed649db0f6dd0159ca478480ae513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Conotoxins - chemistry</topic><topic>Conotoxins - pharmacology</topic><topic>Conus Snail</topic><topic>Inhibitory Concentration 50</topic><topic>Nicotinic Antagonists - chemistry</topic><topic>Nicotinic Antagonists - pharmacology</topic><topic>Oocytes - metabolism</topic><topic>Rats</topic><topic>Receptors, Nicotinic - drug effects</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Luo, Sulan</creatorcontrib><creatorcontrib>Zhangsun, Dongting</creatorcontrib><creatorcontrib>Zhu, Xiaopeng</creatorcontrib><creatorcontrib>Wu, Yong</creatorcontrib><creatorcontrib>Hu, Yuanyan</creatorcontrib><creatorcontrib>Christensen, Sean</creatorcontrib><creatorcontrib>Harvey, Peta J</creatorcontrib><creatorcontrib>Akcan, Muharrem</creatorcontrib><creatorcontrib>Craik, David J</creatorcontrib><creatorcontrib>McIntosh, J. Michael</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Luo, Sulan</au><au>Zhangsun, Dongting</au><au>Zhu, Xiaopeng</au><au>Wu, Yong</au><au>Hu, Yuanyan</au><au>Christensen, Sean</au><au>Harvey, Peta J</au><au>Akcan, Muharrem</au><au>Craik, David J</au><au>McIntosh, J. Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of a Novel α‑Conotoxin TxID from Conus textile That Potently Blocks Rat α3β4 Nicotinic Acetylcholine Receptors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-12-12</date><risdate>2013</risdate><volume>56</volume><issue>23</issue><spage>9655</spage><epage>9663</epage><pages>9655-9663</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The α3β4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an α-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxID blocked rat α3β4 nAChRs with a 12.5 nM IC50, which places it among the most potent α3β4 nAChR antagonists. TxID also blocked the closely related α6/α3β4 with a 94 nM IC50 but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular α-CTx fold but with different surface charge distribution to other 4/6 family members. α-CTx TxID is a novel tool with which to probe the structure and function of α3β4 nAChRs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24200193</pmid><doi>10.1021/jm401254c</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Conotoxins - chemistry Conotoxins - pharmacology Conus Snail Inhibitory Concentration 50 Nicotinic Antagonists - chemistry Nicotinic Antagonists - pharmacology Oocytes - metabolism Rats Receptors, Nicotinic - drug effects Xenopus laevis |
| title | Characterization of a Novel α‑Conotoxin TxID from Conus textile That Potently Blocks Rat α3β4 Nicotinic Acetylcholine Receptors |
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