The RNA Polymerase II Trigger Loop Functions in Substrate Selection and Is Directly Targeted by α-Amanitin
Structural, biochemical, and genetic studies have led to proposals that a mobile element of multisubunit RNA polymerases, the Trigger Loop (TL), plays a critical role in catalysis and can be targeted by antibiotic inhibitors. Here we present evidence that the Saccharomyces cerevisiae RNA Polymerase...
Gespeichert in:
| Veröffentlicht in: | Molecular cell 2008-06, Vol.30 (5), p.547-556 |
|---|---|
| Hauptverfasser: | , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 556 |
|---|---|
| container_issue | 5 |
| container_start_page | 547 |
| container_title | Molecular cell |
| container_volume | 30 |
| creator | Kaplan, Craig D. Larsson, Karl-Magnus Kornberg, Roger D. |
| description | Structural, biochemical, and genetic studies have led to proposals that a mobile element of multisubunit RNA polymerases, the Trigger Loop (TL), plays a critical role in catalysis and can be targeted by antibiotic inhibitors. Here we present evidence that the
Saccharomyces cerevisiae RNA Polymerase II (Pol II) TL participates in substrate selection. Amino acid substitutions within the Pol II TL preferentially alter substrate usage and enzyme fidelity, as does inhibition of transcription by α-amanitin. Finally, substitution of His1085 in the TL specifically renders Pol II highly resistant to α-amanitin, indicating a functional interaction between His1085 and α-amanitin that is supported by rerefinement of an α-amanitin-Pol II crystal structure. We propose that α-amanitin-inhibited Pol II elongation, which is slow and exhibits reduced substrate selectivity, results from direct α-amanitin interference with the TL. |
| doi_str_mv | 10.1016/j.molcel.2008.04.023 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2475549</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1097276508003262</els_id><sourcerecordid>18538653</sourcerecordid><originalsourceid>FETCH-LOGICAL-c461t-1699b8b103e8e9e9a6ed20f6f30a7ec5e2d8a0c20895b88f32d9cb76c6fc11313</originalsourceid><addsrcrecordid>eNp9kFFO4zAQhi0E2nbL3gAhXyBZO3Ec-wWpKgtUqlgE3WfLcSbFJbErO0XqsfYinIlAq4V94WlGM_r_-edD6IySlBLKf67TzrcG2jQjRKSEpSTLj9CYElkmjHJ2fOizkhcj9D3GNSGUFUJ-QyMqilzwIh-jp-Uj4PvbKb7z7a6DoCPg-Rwvg12tIOCF9xt8tXWmt95FbB1-2FaxD7oH_AAtvM-xdjWeR3xpwzBod3ipwwp6qHG1wy9_k2mnne2tO0UnjW4j_DjUCfpz9Ws5u0kWv6_ns-kiMYzTPqFcykpUlOQgQILUHOqMNLzJiS7BFJDVQhOTESGLSogmz2ppqpIb3hhKc5pP0MXed7OtOqgNuCFwqzbBdjrslNdW_b9x9lGt_LPKWFkUTA4GbG9ggo8xQPNPS4l6g6_Wag9fvcFXhKkB_iA7_3z3Q3Sg_REMhu-fLQQVjQVnoH4np2pvv77wCuKHmkI</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>The RNA Polymerase II Trigger Loop Functions in Substrate Selection and Is Directly Targeted by α-Amanitin</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>Elsevier ScienceDirect Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Kaplan, Craig D. ; Larsson, Karl-Magnus ; Kornberg, Roger D.</creator><creatorcontrib>Kaplan, Craig D. ; Larsson, Karl-Magnus ; Kornberg, Roger D.</creatorcontrib><description>Structural, biochemical, and genetic studies have led to proposals that a mobile element of multisubunit RNA polymerases, the Trigger Loop (TL), plays a critical role in catalysis and can be targeted by antibiotic inhibitors. Here we present evidence that the
Saccharomyces cerevisiae RNA Polymerase II (Pol II) TL participates in substrate selection. Amino acid substitutions within the Pol II TL preferentially alter substrate usage and enzyme fidelity, as does inhibition of transcription by α-amanitin. Finally, substitution of His1085 in the TL specifically renders Pol II highly resistant to α-amanitin, indicating a functional interaction between His1085 and α-amanitin that is supported by rerefinement of an α-amanitin-Pol II crystal structure. We propose that α-amanitin-inhibited Pol II elongation, which is slow and exhibits reduced substrate selectivity, results from direct α-amanitin interference with the TL.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2008.04.023</identifier><identifier>PMID: 18538653</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alpha-Amanitin - pharmacology ; Amino Acid Substitution ; DNA ; DNA Transposable Elements - genetics ; Drug Resistance, Fungal - genetics ; Histidine - genetics ; Histidine - metabolism ; Mutation ; Nucleic Acid Synthesis Inhibitors - pharmacology ; Phenotype ; RNA Polymerase II - chemistry ; RNA Polymerase II - genetics ; RNA Polymerase II - metabolism ; Saccharomyces cerevisiae - enzymology ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae - growth & development ; Saccharomyces cerevisiae Proteins - chemistry ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Substrate Specificity ; Transcription, Genetic - drug effects</subject><ispartof>Molecular cell, 2008-06, Vol.30 (5), p.547-556</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-1699b8b103e8e9e9a6ed20f6f30a7ec5e2d8a0c20895b88f32d9cb76c6fc11313</citedby><cites>FETCH-LOGICAL-c461t-1699b8b103e8e9e9a6ed20f6f30a7ec5e2d8a0c20895b88f32d9cb76c6fc11313</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molcel.2008.04.023$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18538653$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaplan, Craig D.</creatorcontrib><creatorcontrib>Larsson, Karl-Magnus</creatorcontrib><creatorcontrib>Kornberg, Roger D.</creatorcontrib><title>The RNA Polymerase II Trigger Loop Functions in Substrate Selection and Is Directly Targeted by α-Amanitin</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Structural, biochemical, and genetic studies have led to proposals that a mobile element of multisubunit RNA polymerases, the Trigger Loop (TL), plays a critical role in catalysis and can be targeted by antibiotic inhibitors. Here we present evidence that the
Saccharomyces cerevisiae RNA Polymerase II (Pol II) TL participates in substrate selection. Amino acid substitutions within the Pol II TL preferentially alter substrate usage and enzyme fidelity, as does inhibition of transcription by α-amanitin. Finally, substitution of His1085 in the TL specifically renders Pol II highly resistant to α-amanitin, indicating a functional interaction between His1085 and α-amanitin that is supported by rerefinement of an α-amanitin-Pol II crystal structure. We propose that α-amanitin-inhibited Pol II elongation, which is slow and exhibits reduced substrate selectivity, results from direct α-amanitin interference with the TL.</description><subject>Alpha-Amanitin - pharmacology</subject><subject>Amino Acid Substitution</subject><subject>DNA</subject><subject>DNA Transposable Elements - genetics</subject><subject>Drug Resistance, Fungal - genetics</subject><subject>Histidine - genetics</subject><subject>Histidine - metabolism</subject><subject>Mutation</subject><subject>Nucleic Acid Synthesis Inhibitors - pharmacology</subject><subject>Phenotype</subject><subject>RNA Polymerase II - chemistry</subject><subject>RNA Polymerase II - genetics</subject><subject>RNA Polymerase II - metabolism</subject><subject>Saccharomyces cerevisiae - enzymology</subject><subject>Saccharomyces cerevisiae - genetics</subject><subject>Saccharomyces cerevisiae - growth & development</subject><subject>Saccharomyces cerevisiae Proteins - chemistry</subject><subject>Saccharomyces cerevisiae Proteins - genetics</subject><subject>Saccharomyces cerevisiae Proteins - metabolism</subject><subject>Substrate Specificity</subject><subject>Transcription, Genetic - drug effects</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kFFO4zAQhi0E2nbL3gAhXyBZO3Ec-wWpKgtUqlgE3WfLcSbFJbErO0XqsfYinIlAq4V94WlGM_r_-edD6IySlBLKf67TzrcG2jQjRKSEpSTLj9CYElkmjHJ2fOizkhcj9D3GNSGUFUJ-QyMqilzwIh-jp-Uj4PvbKb7z7a6DoCPg-Rwvg12tIOCF9xt8tXWmt95FbB1-2FaxD7oH_AAtvM-xdjWeR3xpwzBod3ipwwp6qHG1wy9_k2mnne2tO0UnjW4j_DjUCfpz9Ws5u0kWv6_ns-kiMYzTPqFcykpUlOQgQILUHOqMNLzJiS7BFJDVQhOTESGLSogmz2ppqpIb3hhKc5pP0MXed7OtOqgNuCFwqzbBdjrslNdW_b9x9lGt_LPKWFkUTA4GbG9ggo8xQPNPS4l6g6_Wag9fvcFXhKkB_iA7_3z3Q3Sg_REMhu-fLQQVjQVnoH4np2pvv77wCuKHmkI</recordid><startdate>20080606</startdate><enddate>20080606</enddate><creator>Kaplan, Craig D.</creator><creator>Larsson, Karl-Magnus</creator><creator>Kornberg, Roger D.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>5PM</scope></search><sort><creationdate>20080606</creationdate><title>The RNA Polymerase II Trigger Loop Functions in Substrate Selection and Is Directly Targeted by α-Amanitin</title><author>Kaplan, Craig D. ; Larsson, Karl-Magnus ; Kornberg, Roger D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-1699b8b103e8e9e9a6ed20f6f30a7ec5e2d8a0c20895b88f32d9cb76c6fc11313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Alpha-Amanitin - pharmacology</topic><topic>Amino Acid Substitution</topic><topic>DNA</topic><topic>DNA Transposable Elements - genetics</topic><topic>Drug Resistance, Fungal - genetics</topic><topic>Histidine - genetics</topic><topic>Histidine - metabolism</topic><topic>Mutation</topic><topic>Nucleic Acid Synthesis Inhibitors - pharmacology</topic><topic>Phenotype</topic><topic>RNA Polymerase II - chemistry</topic><topic>RNA Polymerase II - genetics</topic><topic>RNA Polymerase II - metabolism</topic><topic>Saccharomyces cerevisiae - enzymology</topic><topic>Saccharomyces cerevisiae - genetics</topic><topic>Saccharomyces cerevisiae - growth & development</topic><topic>Saccharomyces cerevisiae Proteins - chemistry</topic><topic>Saccharomyces cerevisiae Proteins - genetics</topic><topic>Saccharomyces cerevisiae Proteins - metabolism</topic><topic>Substrate Specificity</topic><topic>Transcription, Genetic - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaplan, Craig D.</creatorcontrib><creatorcontrib>Larsson, Karl-Magnus</creatorcontrib><creatorcontrib>Kornberg, Roger D.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaplan, Craig D.</au><au>Larsson, Karl-Magnus</au><au>Kornberg, Roger D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The RNA Polymerase II Trigger Loop Functions in Substrate Selection and Is Directly Targeted by α-Amanitin</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2008-06-06</date><risdate>2008</risdate><volume>30</volume><issue>5</issue><spage>547</spage><epage>556</epage><pages>547-556</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Structural, biochemical, and genetic studies have led to proposals that a mobile element of multisubunit RNA polymerases, the Trigger Loop (TL), plays a critical role in catalysis and can be targeted by antibiotic inhibitors. Here we present evidence that the
Saccharomyces cerevisiae RNA Polymerase II (Pol II) TL participates in substrate selection. Amino acid substitutions within the Pol II TL preferentially alter substrate usage and enzyme fidelity, as does inhibition of transcription by α-amanitin. Finally, substitution of His1085 in the TL specifically renders Pol II highly resistant to α-amanitin, indicating a functional interaction between His1085 and α-amanitin that is supported by rerefinement of an α-amanitin-Pol II crystal structure. We propose that α-amanitin-inhibited Pol II elongation, which is slow and exhibits reduced substrate selectivity, results from direct α-amanitin interference with the TL.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18538653</pmid><doi>10.1016/j.molcel.2008.04.023</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-2765 |
| ispartof | Molecular cell, 2008-06, Vol.30 (5), p.547-556 |
| issn | 1097-2765 1097-4164 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2475549 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Alpha-Amanitin - pharmacology Amino Acid Substitution DNA DNA Transposable Elements - genetics Drug Resistance, Fungal - genetics Histidine - genetics Histidine - metabolism Mutation Nucleic Acid Synthesis Inhibitors - pharmacology Phenotype RNA Polymerase II - chemistry RNA Polymerase II - genetics RNA Polymerase II - metabolism Saccharomyces cerevisiae - enzymology Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - growth & development Saccharomyces cerevisiae Proteins - chemistry Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Substrate Specificity Transcription, Genetic - drug effects |
| title | The RNA Polymerase II Trigger Loop Functions in Substrate Selection and Is Directly Targeted by α-Amanitin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T05%3A22%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20RNA%20Polymerase%20II%20Trigger%20Loop%20Functions%20in%20Substrate%20Selection%20and%20Is%20Directly%20Targeted%20by%20%CE%B1-Amanitin&rft.jtitle=Molecular%20cell&rft.au=Kaplan,%20Craig%20D.&rft.date=2008-06-06&rft.volume=30&rft.issue=5&rft.spage=547&rft.epage=556&rft.pages=547-556&rft.issn=1097-2765&rft.eissn=1097-4164&rft_id=info:doi/10.1016/j.molcel.2008.04.023&rft_dat=%3Cpubmed_cross%3E18538653%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/18538653&rft_els_id=S1097276508003262&rfr_iscdi=true |