Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase
A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-05, Vol.56 (9), p.3609-3619 |
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| container_end_page | 3619 |
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| container_issue | 9 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 56 |
| creator | Paulsen, Eleonora S Villadsen, Jesper Tenori, Eleonora Liu, Huizhen Bonde, Ditte F Lie, Mette A Bublitz, Maike Olesen, Claus Autzen, Henriette E Dach, Ingrid Sehgal, Pankaj Nissen, Poul Møller, Jesper V Schiøtt, Birgit Christensen, S. Brøgger |
| description | A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors. |
| doi_str_mv | 10.1021/jm4001083 |
| format | Article |
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The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm4001083</identifier><identifier>PMID: 23574308</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Hydrogen Bonding ; Ligands ; Models, Molecular ; Protein Binding ; Protein Conformation ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism ; Thapsigargin - chemical synthesis ; Thapsigargin - chemistry ; Thapsigargin - metabolism ; Water - metabolism</subject><ispartof>Journal of medicinal chemistry, 2013-05, Vol.56 (9), p.3609-3619</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-83d4bbb19dbe037ef72cba0469374584bd3a27f74e1ef8d8a085bfb50007ea153</citedby><cites>FETCH-LOGICAL-a315t-83d4bbb19dbe037ef72cba0469374584bd3a27f74e1ef8d8a085bfb50007ea153</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/jm4001083$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm4001083$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2756,27067,27915,27916,56729,56779</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23574308$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Paulsen, Eleonora S</creatorcontrib><creatorcontrib>Villadsen, Jesper</creatorcontrib><creatorcontrib>Tenori, Eleonora</creatorcontrib><creatorcontrib>Liu, Huizhen</creatorcontrib><creatorcontrib>Bonde, Ditte F</creatorcontrib><creatorcontrib>Lie, Mette A</creatorcontrib><creatorcontrib>Bublitz, Maike</creatorcontrib><creatorcontrib>Olesen, Claus</creatorcontrib><creatorcontrib>Autzen, Henriette E</creatorcontrib><creatorcontrib>Dach, Ingrid</creatorcontrib><creatorcontrib>Sehgal, Pankaj</creatorcontrib><creatorcontrib>Nissen, Poul</creatorcontrib><creatorcontrib>Møller, Jesper V</creatorcontrib><creatorcontrib>Schiøtt, Birgit</creatorcontrib><creatorcontrib>Christensen, S. Brøgger</creatorcontrib><title>Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Hydrogen Bonding</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism</subject><subject>Thapsigargin - chemical synthesis</subject><subject>Thapsigargin - chemistry</subject><subject>Thapsigargin - metabolism</subject><subject>Water - metabolism</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>eNptkE9v1DAUxC0EokvhwBdAuSDBIfT53yY9llWBSkVIUMQxerZfdr1K7GA7B258dIy29MRpZqSfRpph7CWHdxwEvzjOCoBDLx-xDdcCWtWDesw2AEK0YivkGXuW8xEAJBfyKTsTUndKQr9hv39godR-Juercc1NqBFt8THkGsZppWCpKQdq3vvgfNg3cWzuDrhkv8e096EpsfmGycaL6-DiMmGevW2-UvF2nda52eFkfdUrRyFmH6gkvxxiXg5YMNNz9mTEKdOLez1n3z9c3-0-tbdfPt7srm5blFyXtpdOGWP4pTMEsqOxE9YgqO2l7JTulXESRTd2ijiNvesRem1Go-vmjpBrec7enHqXFH-ulMsw-2xpmjBQXPPApQauudrKir49oTbFnBONw5L8jOnXwGH4e_jwcHhlX93XrmYm90D-e7gCr08A2jwc45pCXfmfoj80voj2</recordid><startdate>20130509</startdate><enddate>20130509</enddate><creator>Paulsen, Eleonora S</creator><creator>Villadsen, Jesper</creator><creator>Tenori, Eleonora</creator><creator>Liu, Huizhen</creator><creator>Bonde, Ditte F</creator><creator>Lie, Mette A</creator><creator>Bublitz, Maike</creator><creator>Olesen, Claus</creator><creator>Autzen, Henriette E</creator><creator>Dach, Ingrid</creator><creator>Sehgal, Pankaj</creator><creator>Nissen, Poul</creator><creator>Møller, Jesper V</creator><creator>Schiøtt, Birgit</creator><creator>Christensen, S. 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Brøgger</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-05-09</date><risdate>2013</risdate><volume>56</volume><issue>9</issue><spage>3609</spage><epage>3619</epage><pages>3609-3619</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. 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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Hydrogen Bonding Ligands Models, Molecular Protein Binding Protein Conformation Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism Thapsigargin - chemical synthesis Thapsigargin - chemistry Thapsigargin - metabolism Water - metabolism |
| title | Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase |
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