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The Binding Mode of Epothilone A on α,β-Tubulin by Electron Crystallography
The structure of epothilone A, bound to α,β-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity...
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| Published in: | Science (American Association for the Advancement of Science) 2004-08, Vol.305 (5685), p.866-869 |
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| Main Authors: | , , , , , |
| Format: | Article |
| Language: | English |
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| container_end_page | 869 |
| container_issue | 5685 |
| container_start_page | 866 |
| container_title | Science (American Association for the Advancement of Science) |
| container_volume | 305 |
| creator | Nettles, James H. Li, Huilin Cornett, Ben Krahn, Joseph M. Snyder, James P. Downing, Kenneth H. |
| description | The structure of epothilone A, bound to α,β-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner. |
| doi_str_mv | 10.1126/science.1099190 |
| format | article |
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The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1099190</identifier><identifier>PMID: 15297674</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Antineoplastic agents ; Binding Sites ; Biological and medical sciences ; Cancer ; Cancer treatment ; Care and treatment ; Crystallography ; Crystallography, X-Ray ; Drug interactions ; Electrons ; Epothilones ; Epothilones - chemistry ; Epothilones - metabolism ; Epothilones - pharmacology ; Epoxy compounds ; General aspects ; Hydrogen Bonding ; Hydrogen bonds ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Medical sciences ; Microtubules ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Molecules ; Mutation ; Nuclear Magnetic Resonance, Biomolecular ; Paclitaxel - metabolism ; Pharmacology. Drug treatments ; Phenyls ; Physiological aspects ; Properties ; Protein Conformation ; Stereoisomerism ; Structure-Activity Relationship ; Taxoids ; Thiazoles ; Tubulin - chemistry ; Tubulin - genetics ; Tubulin - metabolism</subject><ispartof>Science (American Association for the Advancement of Science), 2004-08, Vol.305 (5685), p.866-869</ispartof><rights>Copyright 2004 American Association for the Advancement of Science</rights><rights>2004 INIST-CNRS</rights><rights>COPYRIGHT 2004 American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925,33612,33878</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16077811$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15297674$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nettles, James H.</creatorcontrib><creatorcontrib>Li, Huilin</creatorcontrib><creatorcontrib>Cornett, Ben</creatorcontrib><creatorcontrib>Krahn, Joseph M.</creatorcontrib><creatorcontrib>Snyder, James P.</creatorcontrib><creatorcontrib>Downing, Kenneth H.</creatorcontrib><title>The Binding Mode of Epothilone A on α,β-Tubulin by Electron Crystallography</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>The structure of epothilone A, bound to α,β-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.</description><subject>Antineoplastic agents</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Cancer treatment</subject><subject>Care and treatment</subject><subject>Crystallography</subject><subject>Crystallography, X-Ray</subject><subject>Drug interactions</subject><subject>Electrons</subject><subject>Epothilones</subject><subject>Epothilones - chemistry</subject><subject>Epothilones - metabolism</subject><subject>Epothilones - pharmacology</subject><subject>Epoxy compounds</subject><subject>General aspects</subject><subject>Hydrogen Bonding</subject><subject>Hydrogen bonds</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Microtubules</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Molecules</subject><subject>Mutation</subject><subject>Nuclear Magnetic Resonance, Biomolecular</subject><subject>Paclitaxel - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenyls</subject><subject>Physiological aspects</subject><subject>Properties</subject><subject>Protein Conformation</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Taxoids</subject><subject>Thiazoles</subject><subject>Tubulin - chemistry</subject><subject>Tubulin - genetics</subject><subject>Tubulin - metabolism</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqN0t2KEzEUAOBBFLeuXnsjMiAKglPzM5Ofy26pdaFrL6zeDmlyZpolnXQnM2Afa_dB9plMaVUKRUoICTnfORfnJEleYzTEmLDPQVtoNAwxkhJL9CQZxFuRSYLo02SAEGWZQLy4SF6EcItQjEn6PLnABZGc8XyQ3CxWkF7ZxtimTm-8gdRX6WTju5V1voF0lPomfbz_9PiQLfpl72yTLrfpxIHu2hgZt9vQKed83arNavsyeVYpF-DV4bxMfnyZLMZfs9l8ej0ezbK6oLzLDJLECMVyqpEmOQICQIkxGC0N44QJQ4gpBI-7wkpVuTQClOQ0rypJDaOXyYd93U3r73oIXbm2QYNzqgHfh5IxzjERNMJ3e1grB6VtKt-1Su9wOcIESZ4LhqPKTqgaGmjVrguVjc9HfnjCx2VgbfXJhI9HCdF08KurVR9Cef392_l2_vN8ezU924rp7H8NOVjtnYMayjjL8fzYvz3Mo1-uwZSb1q5Vuy3__LMI3h-AClq5qlWNtuGfY4hzgXeF3uzdbeh8-zdOBY0DlfQ3iablWg</recordid><startdate>20040806</startdate><enddate>20040806</enddate><creator>Nettles, James H.</creator><creator>Li, Huilin</creator><creator>Cornett, Ben</creator><creator>Krahn, Joseph M.</creator><creator>Snyder, James P.</creator><creator>Downing, Kenneth H.</creator><general>American Association for the Advancement of Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>8GL</scope><scope>IBG</scope><scope>IOV</scope><scope>ISN</scope><scope>7X8</scope></search><sort><creationdate>20040806</creationdate><title>The Binding Mode of Epothilone A on α,β-Tubulin by Electron Crystallography</title><author>Nettles, James H. ; Li, Huilin ; Cornett, Ben ; Krahn, Joseph M. ; Snyder, James P. ; Downing, Kenneth H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g537t-d092d8a643c0c240e2ee32dd10bd67268d22d587d58f1aaf49d8ea9734ff93d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Antineoplastic agents</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Cancer treatment</topic><topic>Care and treatment</topic><topic>Crystallography</topic><topic>Crystallography, X-Ray</topic><topic>Drug interactions</topic><topic>Electrons</topic><topic>Epothilones</topic><topic>Epothilones - chemistry</topic><topic>Epothilones - metabolism</topic><topic>Epothilones - pharmacology</topic><topic>Epoxy compounds</topic><topic>General aspects</topic><topic>Hydrogen Bonding</topic><topic>Hydrogen bonds</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Microtubules</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Structure</topic><topic>Molecules</topic><topic>Mutation</topic><topic>Nuclear Magnetic Resonance, Biomolecular</topic><topic>Paclitaxel - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenyls</topic><topic>Physiological aspects</topic><topic>Properties</topic><topic>Protein Conformation</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Taxoids</topic><topic>Thiazoles</topic><topic>Tubulin - chemistry</topic><topic>Tubulin - genetics</topic><topic>Tubulin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nettles, James H.</creatorcontrib><creatorcontrib>Li, Huilin</creatorcontrib><creatorcontrib>Cornett, Ben</creatorcontrib><creatorcontrib>Krahn, Joseph M.</creatorcontrib><creatorcontrib>Snyder, James P.</creatorcontrib><creatorcontrib>Downing, Kenneth H.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Gale In Context: High School</collection><collection>Gale In Context: Biography</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>MEDLINE - Academic</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nettles, James H.</au><au>Li, Huilin</au><au>Cornett, Ben</au><au>Krahn, Joseph M.</au><au>Snyder, James P.</au><au>Downing, Kenneth H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Binding Mode of Epothilone A on α,β-Tubulin by Electron Crystallography</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2004-08-06</date><risdate>2004</risdate><volume>305</volume><issue>5685</issue><spage>866</spage><epage>869</epage><pages>866-869</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>The structure of epothilone A, bound to α,β-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.</abstract><cop>Washington, DC</cop><pub>American Association for the Advancement of Science</pub><pmid>15297674</pmid><doi>10.1126/science.1099190</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2004-08, Vol.305 (5685), p.866-869 |
| issn | 0036-8075 1095-9203 |
| language | eng |
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| source | American Association for the Advancement of Science; Social Science Premium Collection; Alma/SFX Local Collection; Education Collection |
| subjects | Antineoplastic agents Binding Sites Biological and medical sciences Cancer Cancer treatment Care and treatment Crystallography Crystallography, X-Ray Drug interactions Electrons Epothilones Epothilones - chemistry Epothilones - metabolism Epothilones - pharmacology Epoxy compounds General aspects Hydrogen Bonding Hydrogen bonds Hydrophobic and Hydrophilic Interactions Ligands Medical sciences Microtubules Models, Molecular Molecular Conformation Molecular Structure Molecules Mutation Nuclear Magnetic Resonance, Biomolecular Paclitaxel - metabolism Pharmacology. Drug treatments Phenyls Physiological aspects Properties Protein Conformation Stereoisomerism Structure-Activity Relationship Taxoids Thiazoles Tubulin - chemistry Tubulin - genetics Tubulin - metabolism |
| title | The Binding Mode of Epothilone A on α,β-Tubulin by Electron Crystallography |
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