Induced Formation of a DNA Bulge Structure by a Molecular Wedge Ligand−Postactivated Neocarzinostatin Chromophore
Our previous structure elucidation of the complexes of DNA and postactivated neocarzinostatin chromophore (NCS-chrom) compounds revealed two distinctly different binding modes of this antitumor molecule. A thorough understanding of these results will provide the molecular basis for the binding and D...
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| Veröffentlicht in: | Biochemistry (Easton) 2002-04, Vol.41 (16), p.5131-5143 |
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| creator | Gao, Xiaolian Stassinopoulos, Adonis Ji, Jie Kwon, Youngjoo Bare, Simona Goldberg, Irving H |
| description | Our previous structure elucidation of the complexes of DNA and postactivated neocarzinostatin chromophore (NCS-chrom) compounds revealed two distinctly different binding modes of this antitumor molecule. A thorough understanding of these results will provide the molecular basis for the binding and DNA chain cleavage properties of NCS-chrom. NCSi-gb is one of the postactivated mimics of NCS-chrom which is formed under thiol-free conditions and is able to bind to DNA. This report describes the structure refinement of the NCSi-gb-bulge-DNA complex [Stassinopoulos, A., Jie, J., Gao, X., and Goldberg, I. H. (1996) Science 272, 1943−1946] and the NMR characterization of the free bulge-DNA and free NCSi-gb. These results reveal that the formation of the complex involves conformational changes in both the DNA and the ligand molecule. Of mechanistic importance for the NCS-chrom−DNA interaction, the two ring systems of the drug are brought closer to each other in the complex. This conformation correlates well with the previously observed marked enhancement of the formation of a DNA bulge cleaving species in the presence of bulge-DNA sequences, due to the promotion of the intramolecular radical quenching of the activated NCS-chrom. Interestingly, the binding of NCSi-gb promotes the formation of a bulge binding pocket; this was not found in the unbound DNA. NCS-chrom is unique among the enediyne antibiotics in its ability to undergo two different mechanisms of activation to form two different DNA binding and cleaving species. The two corresponding DNA complexes are compared. One, the bulge-DNA binder NCSi-gb, involves the major groove, and the second, the duplex binder NCSi-glu which is generated by glutathione-induced activation, involves the minor groove. Since the two NCS-chrom-related ligand molecules contain some common chemical structural elements, such as the carbohydrate ring, the striking differences in their DNA recognition and chain cleavage specificity provide insights into the fundamental principles of DNA recognition and ligand design. |
| doi_str_mv | 10.1021/bi012112o |
| format | Article |
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A thorough understanding of these results will provide the molecular basis for the binding and DNA chain cleavage properties of NCS-chrom. NCSi-gb is one of the postactivated mimics of NCS-chrom which is formed under thiol-free conditions and is able to bind to DNA. This report describes the structure refinement of the NCSi-gb-bulge-DNA complex [Stassinopoulos, A., Jie, J., Gao, X., and Goldberg, I. H. (1996) Science 272, 1943−1946] and the NMR characterization of the free bulge-DNA and free NCSi-gb. These results reveal that the formation of the complex involves conformational changes in both the DNA and the ligand molecule. Of mechanistic importance for the NCS-chrom−DNA interaction, the two ring systems of the drug are brought closer to each other in the complex. This conformation correlates well with the previously observed marked enhancement of the formation of a DNA bulge cleaving species in the presence of bulge-DNA sequences, due to the promotion of the intramolecular radical quenching of the activated NCS-chrom. Interestingly, the binding of NCSi-gb promotes the formation of a bulge binding pocket; this was not found in the unbound DNA. NCS-chrom is unique among the enediyne antibiotics in its ability to undergo two different mechanisms of activation to form two different DNA binding and cleaving species. The two corresponding DNA complexes are compared. One, the bulge-DNA binder NCSi-gb, involves the major groove, and the second, the duplex binder NCSi-glu which is generated by glutathione-induced activation, involves the minor groove. Since the two NCS-chrom-related ligand molecules contain some common chemical structural elements, such as the carbohydrate ring, the striking differences in their DNA recognition and chain cleavage specificity provide insights into the fundamental principles of DNA recognition and ligand design.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi012112o</identifier><identifier>PMID: 11955061</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antibiotics, Antineoplastic - chemistry ; Antibiotics, Antineoplastic - metabolism ; Base Sequence ; Binding Sites ; Computer Simulation ; DNA, Single-Stranded - chemistry ; DNA, Single-Stranded - metabolism ; Enediynes ; Ligands ; Macromolecular Substances ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular - methods ; Nucleic Acid Conformation - drug effects ; Sulfhydryl Reagents - chemistry ; Zinostatin - analogs & derivatives ; Zinostatin - chemistry ; Zinostatin - metabolism</subject><ispartof>Biochemistry (Easton), 2002-04, Vol.41 (16), p.5131-5143</ispartof><rights>Copyright © 2002 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a380t-a708f9b2c59314997d621cfe32645e3ca9bed02499c48e1a09d669b8349d021d3</citedby><cites>FETCH-LOGICAL-a380t-a708f9b2c59314997d621cfe32645e3ca9bed02499c48e1a09d669b8349d021d3</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/bi012112o$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bi012112o$$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/11955061$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gao, Xiaolian</creatorcontrib><creatorcontrib>Stassinopoulos, Adonis</creatorcontrib><creatorcontrib>Ji, Jie</creatorcontrib><creatorcontrib>Kwon, Youngjoo</creatorcontrib><creatorcontrib>Bare, Simona</creatorcontrib><creatorcontrib>Goldberg, Irving H</creatorcontrib><title>Induced Formation of a DNA Bulge Structure by a Molecular Wedge Ligand−Postactivated Neocarzinostatin Chromophore</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>Our previous structure elucidation of the complexes of DNA and postactivated neocarzinostatin chromophore (NCS-chrom) compounds revealed two distinctly different binding modes of this antitumor molecule. A thorough understanding of these results will provide the molecular basis for the binding and DNA chain cleavage properties of NCS-chrom. NCSi-gb is one of the postactivated mimics of NCS-chrom which is formed under thiol-free conditions and is able to bind to DNA. This report describes the structure refinement of the NCSi-gb-bulge-DNA complex [Stassinopoulos, A., Jie, J., Gao, X., and Goldberg, I. H. (1996) Science 272, 1943−1946] and the NMR characterization of the free bulge-DNA and free NCSi-gb. These results reveal that the formation of the complex involves conformational changes in both the DNA and the ligand molecule. Of mechanistic importance for the NCS-chrom−DNA interaction, the two ring systems of the drug are brought closer to each other in the complex. This conformation correlates well with the previously observed marked enhancement of the formation of a DNA bulge cleaving species in the presence of bulge-DNA sequences, due to the promotion of the intramolecular radical quenching of the activated NCS-chrom. Interestingly, the binding of NCSi-gb promotes the formation of a bulge binding pocket; this was not found in the unbound DNA. NCS-chrom is unique among the enediyne antibiotics in its ability to undergo two different mechanisms of activation to form two different DNA binding and cleaving species. The two corresponding DNA complexes are compared. One, the bulge-DNA binder NCSi-gb, involves the major groove, and the second, the duplex binder NCSi-glu which is generated by glutathione-induced activation, involves the minor groove. Since the two NCS-chrom-related ligand molecules contain some common chemical structural elements, such as the carbohydrate ring, the striking differences in their DNA recognition and chain cleavage specificity provide insights into the fundamental principles of DNA recognition and ligand design.</description><subject>Antibiotics, Antineoplastic - chemistry</subject><subject>Antibiotics, Antineoplastic - metabolism</subject><subject>Base Sequence</subject><subject>Binding Sites</subject><subject>Computer Simulation</subject><subject>DNA, Single-Stranded - chemistry</subject><subject>DNA, Single-Stranded - metabolism</subject><subject>Enediynes</subject><subject>Ligands</subject><subject>Macromolecular Substances</subject><subject>Models, Molecular</subject><subject>Nuclear Magnetic Resonance, Biomolecular - methods</subject><subject>Nucleic Acid Conformation - drug effects</subject><subject>Sulfhydryl Reagents - chemistry</subject><subject>Zinostatin - analogs & derivatives</subject><subject>Zinostatin - chemistry</subject><subject>Zinostatin - metabolism</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQxi1ERZfCgRdAvoDEIcXjJHZ8LAsLlZZSsUUcLcd2WpckXvwHUZ6AM4_Ik-BqV-WCxGnk-X76ZvwNQk-AHAOh8LJ3BCgA9ffQAlpKqkaI9j5aEEJYRQUjh-hhjNfl2RDePECHAKJtCYMFiqezydoavPJhUsn5GfsBK_z67AS_yuOlxZsUsk45WNzfFOG9H63Oowr4szVFXrtLNZvfP3-d-5iUTu6bSsXuzHqtwg8333aTm_HyKvjJb698sI_QwaDGaB_v6xH6tHpzsXxXrT-8PV2erCtVdyRVipNuED3Vraih_IgbRkEPtqasaW2tleitIbQouuksKCIMY6Lv6kaUNpj6CD3f-W6D_5ptTHJyUdtxVLP1OUoODEp-4r8gdIzzskABX-xAHXyMwQ5yG9ykwo0EIm9PIe9OUdine9PcT9b8JffZF6DaAS4m-_1OV-GLZLzmrbw438gl_9gC26xkV_hnO17pKK99DnMJ7x-D_wAx9Z-j</recordid><startdate>20020423</startdate><enddate>20020423</enddate><creator>Gao, Xiaolian</creator><creator>Stassinopoulos, Adonis</creator><creator>Ji, Jie</creator><creator>Kwon, Youngjoo</creator><creator>Bare, Simona</creator><creator>Goldberg, Irving H</creator><general>American Chemical Society</general><scope>BSCLL</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>7TM</scope><scope>7X8</scope></search><sort><creationdate>20020423</creationdate><title>Induced Formation of a DNA Bulge Structure by a Molecular Wedge Ligand−Postactivated Neocarzinostatin Chromophore</title><author>Gao, Xiaolian ; Stassinopoulos, Adonis ; Ji, Jie ; Kwon, Youngjoo ; Bare, Simona ; Goldberg, Irving H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a380t-a708f9b2c59314997d621cfe32645e3ca9bed02499c48e1a09d669b8349d021d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Antibiotics, Antineoplastic - chemistry</topic><topic>Antibiotics, Antineoplastic - metabolism</topic><topic>Base Sequence</topic><topic>Binding Sites</topic><topic>Computer Simulation</topic><topic>DNA, Single-Stranded - chemistry</topic><topic>DNA, Single-Stranded - metabolism</topic><topic>Enediynes</topic><topic>Ligands</topic><topic>Macromolecular Substances</topic><topic>Models, Molecular</topic><topic>Nuclear Magnetic Resonance, Biomolecular - methods</topic><topic>Nucleic Acid Conformation - drug effects</topic><topic>Sulfhydryl Reagents - chemistry</topic><topic>Zinostatin - analogs & derivatives</topic><topic>Zinostatin - chemistry</topic><topic>Zinostatin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gao, Xiaolian</creatorcontrib><creatorcontrib>Stassinopoulos, Adonis</creatorcontrib><creatorcontrib>Ji, Jie</creatorcontrib><creatorcontrib>Kwon, Youngjoo</creatorcontrib><creatorcontrib>Bare, Simona</creatorcontrib><creatorcontrib>Goldberg, Irving H</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gao, Xiaolian</au><au>Stassinopoulos, Adonis</au><au>Ji, Jie</au><au>Kwon, Youngjoo</au><au>Bare, Simona</au><au>Goldberg, Irving H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induced Formation of a DNA Bulge Structure by a Molecular Wedge Ligand−Postactivated Neocarzinostatin Chromophore</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2002-04-23</date><risdate>2002</risdate><volume>41</volume><issue>16</issue><spage>5131</spage><epage>5143</epage><pages>5131-5143</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>Our previous structure elucidation of the complexes of DNA and postactivated neocarzinostatin chromophore (NCS-chrom) compounds revealed two distinctly different binding modes of this antitumor molecule. A thorough understanding of these results will provide the molecular basis for the binding and DNA chain cleavage properties of NCS-chrom. NCSi-gb is one of the postactivated mimics of NCS-chrom which is formed under thiol-free conditions and is able to bind to DNA. This report describes the structure refinement of the NCSi-gb-bulge-DNA complex [Stassinopoulos, A., Jie, J., Gao, X., and Goldberg, I. H. (1996) Science 272, 1943−1946] and the NMR characterization of the free bulge-DNA and free NCSi-gb. These results reveal that the formation of the complex involves conformational changes in both the DNA and the ligand molecule. Of mechanistic importance for the NCS-chrom−DNA interaction, the two ring systems of the drug are brought closer to each other in the complex. This conformation correlates well with the previously observed marked enhancement of the formation of a DNA bulge cleaving species in the presence of bulge-DNA sequences, due to the promotion of the intramolecular radical quenching of the activated NCS-chrom. Interestingly, the binding of NCSi-gb promotes the formation of a bulge binding pocket; this was not found in the unbound DNA. NCS-chrom is unique among the enediyne antibiotics in its ability to undergo two different mechanisms of activation to form two different DNA binding and cleaving species. The two corresponding DNA complexes are compared. One, the bulge-DNA binder NCSi-gb, involves the major groove, and the second, the duplex binder NCSi-glu which is generated by glutathione-induced activation, involves the minor groove. Since the two NCS-chrom-related ligand molecules contain some common chemical structural elements, such as the carbohydrate ring, the striking differences in their DNA recognition and chain cleavage specificity provide insights into the fundamental principles of DNA recognition and ligand design.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>11955061</pmid><doi>10.1021/bi012112o</doi><tpages>13</tpages></addata></record> |
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| subjects | Antibiotics, Antineoplastic - chemistry Antibiotics, Antineoplastic - metabolism Base Sequence Binding Sites Computer Simulation DNA, Single-Stranded - chemistry DNA, Single-Stranded - metabolism Enediynes Ligands Macromolecular Substances Models, Molecular Nuclear Magnetic Resonance, Biomolecular - methods Nucleic Acid Conformation - drug effects Sulfhydryl Reagents - chemistry Zinostatin - analogs & derivatives Zinostatin - chemistry Zinostatin - metabolism |
| title | Induced Formation of a DNA Bulge Structure by a Molecular Wedge Ligand−Postactivated Neocarzinostatin Chromophore |
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