Gaba Receptor Insecticide Non-Competitive Antagonists May Bind at Allosteric Modulator Sites
Results from several studies have shown that a series of chemically distinct insecticide compounds (picrotoxin, BIDN, TBPS, fipronil, lindane, EBOB, and α-endosulfan) affect GABAA receptor function. In this investigation, docking of this set of insecticides to the GABA receptor identified five poten...
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| Veröffentlicht in: | International journal of neuroscience 2008-05, Vol.118 (5), p.705-734 |
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| container_title | International journal of neuroscience |
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| creator | Law, Richard J. Lightstone, Felice C. |
| description | Results from several studies have shown that a series of chemically distinct insecticide compounds (picrotoxin, BIDN, TBPS, fipronil, lindane, EBOB, and α-endosulfan) affect GABAA receptor function. In this investigation, docking of this set of insecticides to the GABA receptor identified five potential binding sites. The lowest energy site was found within the base of the transmembrane bundle, interacting with M2 but not in the pore, and includes many of the residues previously experimentally implicated in insecticide binding. Many of the binding modes are suggestive of a non-competitive allosteric mechanism based on interruption of the channel gating mechanism rather than directly blocking the channel. The results also distinguished between isomers of hexachlorohexane (HCH), where γ-HCH (lindane) binds more favorably than β-HCH. The results suggest multiple sites for insecticide binding and may suggest further mutagenesis and labeling work to either confirm or rule out these findings. |
| doi_str_mv | 10.1080/00207450701750216 |
| format | Article |
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In this investigation, docking of this set of insecticides to the GABA receptor identified five potential binding sites. The lowest energy site was found within the base of the transmembrane bundle, interacting with M2 but not in the pore, and includes many of the residues previously experimentally implicated in insecticide binding. Many of the binding modes are suggestive of a non-competitive allosteric mechanism based on interruption of the channel gating mechanism rather than directly blocking the channel. The results also distinguished between isomers of hexachlorohexane (HCH), where γ-HCH (lindane) binds more favorably than β-HCH. The results suggest multiple sites for insecticide binding and may suggest further mutagenesis and labeling work to either confirm or rule out these findings.</description><identifier>ISSN: 0020-7454</identifier><identifier>EISSN: 1563-5279</identifier><identifier>EISSN: 1543-5245</identifier><identifier>DOI: 10.1080/00207450701750216</identifier><identifier>PMID: 18446586</identifier><language>eng</language><publisher>England: Informa UK Ltd</publisher><subject>Allosteric Site - drug effects ; Animals ; BIDN ; Binding Sites - drug effects ; Binding, Competitive - drug effects ; Computer Simulation ; EBOB and α-endosulfan ; fipronil ; GABA receptor ; Insecticides - pharmacology ; lindane ; Models, Chemical ; Models, Structural ; picrotoxin ; Protein Subunits ; Receptors, GABA-A - chemistry ; Receptors, GABA-A - drug effects ; Receptors, GABA-A - physiology ; TBPS</subject><ispartof>International journal of neuroscience, 2008-05, Vol.118 (5), p.705-734</ispartof><rights>2008 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-85bd2d57e1a62c1617ae8326b1921a4b00375aa5222f36d677763c9d325e76613</citedby><cites>FETCH-LOGICAL-c435t-85bd2d57e1a62c1617ae8326b1921a4b00375aa5222f36d677763c9d325e76613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.1080/00207450701750216$$EPDF$$P50$$Ginformaworld$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.1080/00207450701750216$$EHTML$$P50$$Ginformaworld$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,59623,59729,60412,60518,61197,61232,61378,61413</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18446586$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Law, Richard J.</creatorcontrib><creatorcontrib>Lightstone, Felice C.</creatorcontrib><title>Gaba Receptor Insecticide Non-Competitive Antagonists May Bind at Allosteric Modulator Sites</title><title>International journal of neuroscience</title><addtitle>Int J Neurosci</addtitle><description>Results from several studies have shown that a series of chemically distinct insecticide compounds (picrotoxin, BIDN, TBPS, fipronil, lindane, EBOB, and α-endosulfan) affect GABAA receptor function. In this investigation, docking of this set of insecticides to the GABA receptor identified five potential binding sites. The lowest energy site was found within the base of the transmembrane bundle, interacting with M2 but not in the pore, and includes many of the residues previously experimentally implicated in insecticide binding. Many of the binding modes are suggestive of a non-competitive allosteric mechanism based on interruption of the channel gating mechanism rather than directly blocking the channel. The results also distinguished between isomers of hexachlorohexane (HCH), where γ-HCH (lindane) binds more favorably than β-HCH. The results suggest multiple sites for insecticide binding and may suggest further mutagenesis and labeling work to either confirm or rule out these findings.</description><subject>Allosteric Site - drug effects</subject><subject>Animals</subject><subject>BIDN</subject><subject>Binding Sites - drug effects</subject><subject>Binding, Competitive - drug effects</subject><subject>Computer Simulation</subject><subject>EBOB and α-endosulfan</subject><subject>fipronil</subject><subject>GABA receptor</subject><subject>Insecticides - pharmacology</subject><subject>lindane</subject><subject>Models, Chemical</subject><subject>Models, Structural</subject><subject>picrotoxin</subject><subject>Protein Subunits</subject><subject>Receptors, GABA-A - chemistry</subject><subject>Receptors, GABA-A - drug effects</subject><subject>Receptors, GABA-A - physiology</subject><subject>TBPS</subject><issn>0020-7454</issn><issn>1563-5279</issn><issn>1543-5245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kFuLFDEQRoMo7rDuD_BF8uRbu7l0km70ZRzcC-wFvLwJoTpd7Ua6kzFJK_Pvt4cZEBH2qSjqfIfiI-Q1Z-84a9g5Y4KZWjHDuFFMcP2MrLjSslLCtM_Jan-vFqA-IWc5-27ZZduKpnlJTnhT11o1ekW-X0IH9DM63JaY6HXI6Ip3vkd6F0O1idMWiy_-N9J1KPAjBp9Lprewox996CkUuh7HmAsm7-ht7OcR9qIvvmB-RV4MMGY8O85T8u3i09fNVXVzf3m9Wd9UrpaqVI3qetErgxy0cFxzA9hIoTveCg718rk0CkAJIQape22M0dK1vRQKjdZcnpK3B-82xV8z5mInnx2OIwSMc7aC7w28XkB-AF2KOScc7Db5CdLOcmb3rdr_Wl0yb47yuZuw_5s4drgAHw6AD0NME_yJaextgd0Y05AgOJ-tfMr__p_4A8JYHhwktD_jnMJS3BPfPQLZK5Xx</recordid><startdate>200805</startdate><enddate>200805</enddate><creator>Law, Richard J.</creator><creator>Lightstone, Felice C.</creator><general>Informa UK Ltd</general><general>Taylor & Francis</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><scope>7TK</scope></search><sort><creationdate>200805</creationdate><title>Gaba Receptor Insecticide Non-Competitive Antagonists May Bind at Allosteric Modulator Sites</title><author>Law, Richard J. ; Lightstone, Felice C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-85bd2d57e1a62c1617ae8326b1921a4b00375aa5222f36d677763c9d325e76613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Allosteric Site - drug effects</topic><topic>Animals</topic><topic>BIDN</topic><topic>Binding Sites - drug effects</topic><topic>Binding, Competitive - drug effects</topic><topic>Computer Simulation</topic><topic>EBOB and α-endosulfan</topic><topic>fipronil</topic><topic>GABA receptor</topic><topic>Insecticides - pharmacology</topic><topic>lindane</topic><topic>Models, Chemical</topic><topic>Models, Structural</topic><topic>picrotoxin</topic><topic>Protein Subunits</topic><topic>Receptors, GABA-A - chemistry</topic><topic>Receptors, GABA-A - drug effects</topic><topic>Receptors, GABA-A - physiology</topic><topic>TBPS</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Law, Richard J.</creatorcontrib><creatorcontrib>Lightstone, Felice C.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>International journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Law, Richard J.</au><au>Lightstone, Felice C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gaba Receptor Insecticide Non-Competitive Antagonists May Bind at Allosteric Modulator Sites</atitle><jtitle>International journal of neuroscience</jtitle><addtitle>Int J Neurosci</addtitle><date>2008-05</date><risdate>2008</risdate><volume>118</volume><issue>5</issue><spage>705</spage><epage>734</epage><pages>705-734</pages><issn>0020-7454</issn><eissn>1563-5279</eissn><eissn>1543-5245</eissn><abstract>Results from several studies have shown that a series of chemically distinct insecticide compounds (picrotoxin, BIDN, TBPS, fipronil, lindane, EBOB, and α-endosulfan) affect GABAA receptor function. In this investigation, docking of this set of insecticides to the GABA receptor identified five potential binding sites. The lowest energy site was found within the base of the transmembrane bundle, interacting with M2 but not in the pore, and includes many of the residues previously experimentally implicated in insecticide binding. Many of the binding modes are suggestive of a non-competitive allosteric mechanism based on interruption of the channel gating mechanism rather than directly blocking the channel. The results also distinguished between isomers of hexachlorohexane (HCH), where γ-HCH (lindane) binds more favorably than β-HCH. The results suggest multiple sites for insecticide binding and may suggest further mutagenesis and labeling work to either confirm or rule out these findings.</abstract><cop>England</cop><pub>Informa UK Ltd</pub><pmid>18446586</pmid><doi>10.1080/00207450701750216</doi><tpages>30</tpages></addata></record> |
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| ispartof | International journal of neuroscience, 2008-05, Vol.118 (5), p.705-734 |
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| source | MEDLINE; Taylor & Francis Medical Library - CRKN; Taylor & Francis Journals Complete |
| subjects | Allosteric Site - drug effects Animals BIDN Binding Sites - drug effects Binding, Competitive - drug effects Computer Simulation EBOB and α-endosulfan fipronil GABA receptor Insecticides - pharmacology lindane Models, Chemical Models, Structural picrotoxin Protein Subunits Receptors, GABA-A - chemistry Receptors, GABA-A - drug effects Receptors, GABA-A - physiology TBPS |
| title | Gaba Receptor Insecticide Non-Competitive Antagonists May Bind at Allosteric Modulator Sites |
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