Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα)
1‐[(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydronaphthalen‐2‐yl)amino]benzotriazole‐5‐carboxylic acid (CBt‐PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of exist...
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| Veröffentlicht in: | FEBS letters 2019-01, Vol.593 (2), p.242-250 |
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| creator | Miyashita, Yurina Numoto, Nobutaka Arulmozhiraja, Sundaram Nakano, Shogo Matsuo, Naoya Shimizu, Kanade Shibahara, Osamu Fujihara, Michiko Kakuta, Hiroki Ito, Sohei Ikura, Teikichi Ito, Nobutoshi Tokiwa, Hiroaki |
| description | 1‐[(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydronaphthalen‐2‐yl)amino]benzotriazole‐5‐carboxylic acid (CBt‐PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt‐PMN‐bound ligand‐binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt‐PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt‐PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF‐2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt‐PMN in the complex is probably the reason behind its partial agonistic activity. |
| doi_str_mv | 10.1002/1873-3468.13301 |
| format | Article |
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Herein, we report the crystal structure of CBt‐PMN‐bound ligand‐binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt‐PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt‐PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF‐2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt‐PMN in the complex is probably the reason behind its partial agonistic activity.</description><identifier>ISSN: 0014-5793</identifier><identifier>EISSN: 1873-3468</identifier><identifier>DOI: 10.1002/1873-3468.13301</identifier><identifier>PMID: 30565665</identifier><language>eng</language><publisher>England</publisher><subject>Binding Sites ; biochemical analysis ; crystal structure ; Crystallography, X-Ray ; fragment molecular orbital theory ; Humans ; Ligands ; Models, Molecular ; Molecular Conformation ; Molecular Dynamics Simulation ; molecular dynamics simulations ; partial agonist ; Protein Binding ; Retinoid X Receptor alpha - chemistry ; Retinoid X Receptor alpha - metabolism ; RXRα ; Tetrahydronaphthalenes - chemistry ; Tetrahydronaphthalenes - pharmacology ; Triazoles - chemistry ; Triazoles - pharmacology</subject><ispartof>FEBS letters, 2019-01, Vol.593 (2), p.242-250</ispartof><rights>2018 Federation of European Biochemical Societies</rights><rights>2018 Federation of European Biochemical Societies.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3851-cb75dfbe9639c20b211b7eebe4ab46efde66cd1ecb22e4f692fae97ce9ef9f753</citedby><cites>FETCH-LOGICAL-c3851-cb75dfbe9639c20b211b7eebe4ab46efde66cd1ecb22e4f692fae97ce9ef9f753</cites><orcidid>0000-0002-7150-560X ; 0000-0002-6614-7158 ; 0000-0002-3790-1799 ; 0000-0002-3633-8121 ; 0000-0003-0839-0384 ; 0000-0002-9937-3100 ; 0000-0003-2736-4413</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2F1873-3468.13301$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2F1873-3468.13301$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30565665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miyashita, Yurina</creatorcontrib><creatorcontrib>Numoto, Nobutaka</creatorcontrib><creatorcontrib>Arulmozhiraja, Sundaram</creatorcontrib><creatorcontrib>Nakano, Shogo</creatorcontrib><creatorcontrib>Matsuo, Naoya</creatorcontrib><creatorcontrib>Shimizu, Kanade</creatorcontrib><creatorcontrib>Shibahara, Osamu</creatorcontrib><creatorcontrib>Fujihara, Michiko</creatorcontrib><creatorcontrib>Kakuta, Hiroki</creatorcontrib><creatorcontrib>Ito, Sohei</creatorcontrib><creatorcontrib>Ikura, Teikichi</creatorcontrib><creatorcontrib>Ito, Nobutoshi</creatorcontrib><creatorcontrib>Tokiwa, Hiroaki</creatorcontrib><title>Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα)</title><title>FEBS letters</title><addtitle>FEBS Lett</addtitle><description>1‐[(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydronaphthalen‐2‐yl)amino]benzotriazole‐5‐carboxylic acid (CBt‐PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt‐PMN‐bound ligand‐binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt‐PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt‐PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF‐2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt‐PMN in the complex is probably the reason behind its partial agonistic activity.</description><subject>Binding Sites</subject><subject>biochemical analysis</subject><subject>crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>fragment molecular orbital theory</subject><subject>Humans</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Dynamics Simulation</subject><subject>molecular dynamics simulations</subject><subject>partial agonist</subject><subject>Protein Binding</subject><subject>Retinoid X Receptor alpha - chemistry</subject><subject>Retinoid X Receptor alpha - metabolism</subject><subject>RXRα</subject><subject>Tetrahydronaphthalenes - chemistry</subject><subject>Tetrahydronaphthalenes - pharmacology</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacology</subject><issn>0014-5793</issn><issn>1873-3468</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMtOwzAQRS0EgvJYs0NelkXAjmMnWfIoD6kSEgKpO8txxsUojYvtgPpZ_Ei_ifQBW1Yzc3XmLg5Cp5RcUELSS1rkLGGZKC4oY4TuoMFfsosGhNAs4XnJDtBhCO-kvwta7qMDRrjgQvABervtVIO1a43zMxWta7EzOL4BbuxUtTW2bd1pCOtorny0Pa6mrrUhWo2VjvbTxsXqyUO0rbM1nvSrhnl0Hi-_8fB58rz8Pj9Ge0Y1AU628wi93o1ebh6S8dP9483VONGs4DTRVc5rU0EpWKlTUqWUVjlABZmqMgGmBiF0TUFXaQqZEWVqFJS5hhJMaXLOjtBw0zv37qODEOXMBg1No1pwXZAp5QXnBSNZj15uUO1dCB6MnHs7U34hKZErvXIlU65kyrXe_uNsW95VM6j_-F-fPSA2wJdtYPFfn7wbXaeb5h8uWIei</recordid><startdate>201901</startdate><enddate>201901</enddate><creator>Miyashita, Yurina</creator><creator>Numoto, Nobutaka</creator><creator>Arulmozhiraja, Sundaram</creator><creator>Nakano, Shogo</creator><creator>Matsuo, Naoya</creator><creator>Shimizu, Kanade</creator><creator>Shibahara, Osamu</creator><creator>Fujihara, Michiko</creator><creator>Kakuta, Hiroki</creator><creator>Ito, Sohei</creator><creator>Ikura, Teikichi</creator><creator>Ito, Nobutoshi</creator><creator>Tokiwa, Hiroaki</creator><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>7X8</scope><orcidid>https://orcid.org/0000-0002-7150-560X</orcidid><orcidid>https://orcid.org/0000-0002-6614-7158</orcidid><orcidid>https://orcid.org/0000-0002-3790-1799</orcidid><orcidid>https://orcid.org/0000-0002-3633-8121</orcidid><orcidid>https://orcid.org/0000-0003-0839-0384</orcidid><orcidid>https://orcid.org/0000-0002-9937-3100</orcidid><orcidid>https://orcid.org/0000-0003-2736-4413</orcidid></search><sort><creationdate>201901</creationdate><title>Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα)</title><author>Miyashita, Yurina ; Numoto, Nobutaka ; Arulmozhiraja, Sundaram ; Nakano, Shogo ; Matsuo, Naoya ; Shimizu, Kanade ; Shibahara, Osamu ; Fujihara, Michiko ; Kakuta, Hiroki ; Ito, Sohei ; Ikura, Teikichi ; Ito, Nobutoshi ; Tokiwa, Hiroaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3851-cb75dfbe9639c20b211b7eebe4ab46efde66cd1ecb22e4f692fae97ce9ef9f753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Binding Sites</topic><topic>biochemical analysis</topic><topic>crystal structure</topic><topic>Crystallography, X-Ray</topic><topic>fragment molecular orbital theory</topic><topic>Humans</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Dynamics Simulation</topic><topic>molecular dynamics simulations</topic><topic>partial agonist</topic><topic>Protein Binding</topic><topic>Retinoid X Receptor alpha - chemistry</topic><topic>Retinoid X Receptor alpha - metabolism</topic><topic>RXRα</topic><topic>Tetrahydronaphthalenes - chemistry</topic><topic>Tetrahydronaphthalenes - pharmacology</topic><topic>Triazoles - chemistry</topic><topic>Triazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miyashita, Yurina</creatorcontrib><creatorcontrib>Numoto, Nobutaka</creatorcontrib><creatorcontrib>Arulmozhiraja, Sundaram</creatorcontrib><creatorcontrib>Nakano, Shogo</creatorcontrib><creatorcontrib>Matsuo, Naoya</creatorcontrib><creatorcontrib>Shimizu, Kanade</creatorcontrib><creatorcontrib>Shibahara, Osamu</creatorcontrib><creatorcontrib>Fujihara, Michiko</creatorcontrib><creatorcontrib>Kakuta, Hiroki</creatorcontrib><creatorcontrib>Ito, Sohei</creatorcontrib><creatorcontrib>Ikura, Teikichi</creatorcontrib><creatorcontrib>Ito, Nobutoshi</creatorcontrib><creatorcontrib>Tokiwa, Hiroaki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>FEBS letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miyashita, Yurina</au><au>Numoto, Nobutaka</au><au>Arulmozhiraja, Sundaram</au><au>Nakano, Shogo</au><au>Matsuo, Naoya</au><au>Shimizu, Kanade</au><au>Shibahara, Osamu</au><au>Fujihara, Michiko</au><au>Kakuta, Hiroki</au><au>Ito, Sohei</au><au>Ikura, Teikichi</au><au>Ito, Nobutoshi</au><au>Tokiwa, Hiroaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα)</atitle><jtitle>FEBS letters</jtitle><addtitle>FEBS Lett</addtitle><date>2019-01</date><risdate>2019</risdate><volume>593</volume><issue>2</issue><spage>242</spage><epage>250</epage><pages>242-250</pages><issn>0014-5793</issn><eissn>1873-3468</eissn><abstract>1‐[(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydronaphthalen‐2‐yl)amino]benzotriazole‐5‐carboxylic acid (CBt‐PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt‐PMN‐bound ligand‐binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt‐PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt‐PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF‐2 interface depends on the conformation of the ligand. 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| source | MEDLINE; Wiley Free Content; EZB-FREE-00999 freely available EZB journals; Wiley Online Library All Journals; Alma/SFX Local Collection |
| subjects | Binding Sites biochemical analysis crystal structure Crystallography, X-Ray fragment molecular orbital theory Humans Ligands Models, Molecular Molecular Conformation Molecular Dynamics Simulation molecular dynamics simulations partial agonist Protein Binding Retinoid X Receptor alpha - chemistry Retinoid X Receptor alpha - metabolism RXRα Tetrahydronaphthalenes - chemistry Tetrahydronaphthalenes - pharmacology Triazoles - chemistry Triazoles - pharmacology |
| title | Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα) |
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