Crystal Structure of the Human Cannabinoid Receptor CB 1
Cannabinoid receptor 1 (CB ) is the principal target of Δ -tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB is activated by endocannabinoids and is a promising therapeutic target for pain...
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| Veröffentlicht in: | Cell 2016-10, Vol.167 (3), p.750 |
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| container_title | Cell |
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| creator | Hua, Tian Vemuri, Kiran Pu, Mengchen Qu, Lu Han, Gye Won Wu, Yiran Zhao, Suwen Shui, Wenqing Li, Shanshan Korde, Anisha Laprairie, Robert B Stahl, Edward L Ho, Jo-Hao Zvonok, Nikolai Zhou, Han Kufareva, Irina Wu, Beili Zhao, Qiang Hanson, Michael A Bohn, Laura M Makriyannis, Alexandros Stevens, Raymond C Liu, Zhi-Jie |
| description | Cannabinoid receptor 1 (CB
) is the principal target of Δ
-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB
is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB
in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB
-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB
ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB
and provides new opportunities for the design of next-generation CB
-targeting pharmaceuticals. |
| doi_str_mv | 10.1016/j.cell.2016.10.004 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmed_primary_27768894</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>27768894</sourcerecordid><originalsourceid>FETCH-pubmed_primary_277688943</originalsourceid><addsrcrecordid>eNqFjbsOgjAARRsTI_j4AQfTH6C2CLSsNhpmdScFSoSUQvoY-HsZdHa6JycnuQAcCUYEk-zco1oqheKFF4EwTlYgJDinUUJoHICttT3GmKVpugFBTGnGWJ6EgHEzWycUfDrja-eNhGML3VvCwg9CQy60FlWnx66BD1nLyY0G8iske7BuhbLy8N0dON1vL15Ek68G2ZST6QZh5vJ3dfkbfAAu-DjZ</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Crystal Structure of the Human Cannabinoid Receptor CB 1</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><source>Cell Press Free Archives</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Hua, Tian ; Vemuri, Kiran ; Pu, Mengchen ; Qu, Lu ; Han, Gye Won ; Wu, Yiran ; Zhao, Suwen ; Shui, Wenqing ; Li, Shanshan ; Korde, Anisha ; Laprairie, Robert B ; Stahl, Edward L ; Ho, Jo-Hao ; Zvonok, Nikolai ; Zhou, Han ; Kufareva, Irina ; Wu, Beili ; Zhao, Qiang ; Hanson, Michael A ; Bohn, Laura M ; Makriyannis, Alexandros ; Stevens, Raymond C ; Liu, Zhi-Jie</creator><creatorcontrib>Hua, Tian ; Vemuri, Kiran ; Pu, Mengchen ; Qu, Lu ; Han, Gye Won ; Wu, Yiran ; Zhao, Suwen ; Shui, Wenqing ; Li, Shanshan ; Korde, Anisha ; Laprairie, Robert B ; Stahl, Edward L ; Ho, Jo-Hao ; Zvonok, Nikolai ; Zhou, Han ; Kufareva, Irina ; Wu, Beili ; Zhao, Qiang ; Hanson, Michael A ; Bohn, Laura M ; Makriyannis, Alexandros ; Stevens, Raymond C ; Liu, Zhi-Jie</creatorcontrib><description>Cannabinoid receptor 1 (CB
) is the principal target of Δ
-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB
is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB
in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB
-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB
ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB
and provides new opportunities for the design of next-generation CB
-targeting pharmaceuticals.</description><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2016.10.004</identifier><identifier>PMID: 27768894</identifier><language>eng</language><publisher>United States</publisher><subject>Binding Sites ; Cannabinoid Receptor Antagonists - chemistry ; Cannabinoids - pharmacology ; Cannabis - chemistry ; Crystallography, X-Ray ; Dronabinol - pharmacology ; Endocannabinoids - pharmacology ; Humans ; Ligands ; Morpholines - chemical synthesis ; Morpholines - chemistry ; Protein Binding ; Protein Conformation, alpha-Helical ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Receptor, Cannabinoid, CB1 - antagonists & inhibitors ; Receptor, Cannabinoid, CB1 - chemistry</subject><ispartof>Cell, 2016-10, Vol.167 (3), p.750</ispartof><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27768894$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hua, Tian</creatorcontrib><creatorcontrib>Vemuri, Kiran</creatorcontrib><creatorcontrib>Pu, Mengchen</creatorcontrib><creatorcontrib>Qu, Lu</creatorcontrib><creatorcontrib>Han, Gye Won</creatorcontrib><creatorcontrib>Wu, Yiran</creatorcontrib><creatorcontrib>Zhao, Suwen</creatorcontrib><creatorcontrib>Shui, Wenqing</creatorcontrib><creatorcontrib>Li, Shanshan</creatorcontrib><creatorcontrib>Korde, Anisha</creatorcontrib><creatorcontrib>Laprairie, Robert B</creatorcontrib><creatorcontrib>Stahl, Edward L</creatorcontrib><creatorcontrib>Ho, Jo-Hao</creatorcontrib><creatorcontrib>Zvonok, Nikolai</creatorcontrib><creatorcontrib>Zhou, Han</creatorcontrib><creatorcontrib>Kufareva, Irina</creatorcontrib><creatorcontrib>Wu, Beili</creatorcontrib><creatorcontrib>Zhao, Qiang</creatorcontrib><creatorcontrib>Hanson, Michael A</creatorcontrib><creatorcontrib>Bohn, Laura M</creatorcontrib><creatorcontrib>Makriyannis, Alexandros</creatorcontrib><creatorcontrib>Stevens, Raymond C</creatorcontrib><creatorcontrib>Liu, Zhi-Jie</creatorcontrib><title>Crystal Structure of the Human Cannabinoid Receptor CB 1</title><title>Cell</title><addtitle>Cell</addtitle><description>Cannabinoid receptor 1 (CB
) is the principal target of Δ
-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB
is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB
in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB
-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB
ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB
and provides new opportunities for the design of next-generation CB
-targeting pharmaceuticals.</description><subject>Binding Sites</subject><subject>Cannabinoid Receptor Antagonists - chemistry</subject><subject>Cannabinoids - pharmacology</subject><subject>Cannabis - chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Dronabinol - pharmacology</subject><subject>Endocannabinoids - pharmacology</subject><subject>Humans</subject><subject>Ligands</subject><subject>Morpholines - chemical synthesis</subject><subject>Morpholines - chemistry</subject><subject>Protein Binding</subject><subject>Protein Conformation, alpha-Helical</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Receptor, Cannabinoid, CB1 - antagonists & inhibitors</subject><subject>Receptor, Cannabinoid, CB1 - chemistry</subject><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjbsOgjAARRsTI_j4AQfTH6C2CLSsNhpmdScFSoSUQvoY-HsZdHa6JycnuQAcCUYEk-zco1oqheKFF4EwTlYgJDinUUJoHICttT3GmKVpugFBTGnGWJ6EgHEzWycUfDrja-eNhGML3VvCwg9CQy60FlWnx66BD1nLyY0G8iske7BuhbLy8N0dON1vL15Ek68G2ZST6QZh5vJ3dfkbfAAu-DjZ</recordid><startdate>20161020</startdate><enddate>20161020</enddate><creator>Hua, Tian</creator><creator>Vemuri, Kiran</creator><creator>Pu, Mengchen</creator><creator>Qu, Lu</creator><creator>Han, Gye Won</creator><creator>Wu, Yiran</creator><creator>Zhao, Suwen</creator><creator>Shui, Wenqing</creator><creator>Li, Shanshan</creator><creator>Korde, Anisha</creator><creator>Laprairie, Robert B</creator><creator>Stahl, Edward L</creator><creator>Ho, Jo-Hao</creator><creator>Zvonok, Nikolai</creator><creator>Zhou, Han</creator><creator>Kufareva, Irina</creator><creator>Wu, Beili</creator><creator>Zhao, Qiang</creator><creator>Hanson, Michael A</creator><creator>Bohn, Laura M</creator><creator>Makriyannis, Alexandros</creator><creator>Stevens, Raymond C</creator><creator>Liu, Zhi-Jie</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20161020</creationdate><title>Crystal Structure of the Human Cannabinoid Receptor CB 1</title><author>Hua, Tian ; Vemuri, Kiran ; Pu, Mengchen ; Qu, Lu ; Han, Gye Won ; Wu, Yiran ; Zhao, Suwen ; Shui, Wenqing ; Li, Shanshan ; Korde, Anisha ; Laprairie, Robert B ; Stahl, Edward L ; Ho, Jo-Hao ; Zvonok, Nikolai ; Zhou, Han ; Kufareva, Irina ; Wu, Beili ; Zhao, Qiang ; Hanson, Michael A ; Bohn, Laura M ; Makriyannis, Alexandros ; Stevens, Raymond C ; Liu, Zhi-Jie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_277688943</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Binding Sites</topic><topic>Cannabinoid Receptor Antagonists - chemistry</topic><topic>Cannabinoids - pharmacology</topic><topic>Cannabis - chemistry</topic><topic>Crystallography, X-Ray</topic><topic>Dronabinol - pharmacology</topic><topic>Endocannabinoids - pharmacology</topic><topic>Humans</topic><topic>Ligands</topic><topic>Morpholines - chemical synthesis</topic><topic>Morpholines - chemistry</topic><topic>Protein Binding</topic><topic>Protein Conformation, alpha-Helical</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Receptor, Cannabinoid, CB1 - antagonists & inhibitors</topic><topic>Receptor, Cannabinoid, CB1 - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hua, Tian</creatorcontrib><creatorcontrib>Vemuri, Kiran</creatorcontrib><creatorcontrib>Pu, Mengchen</creatorcontrib><creatorcontrib>Qu, Lu</creatorcontrib><creatorcontrib>Han, Gye Won</creatorcontrib><creatorcontrib>Wu, Yiran</creatorcontrib><creatorcontrib>Zhao, Suwen</creatorcontrib><creatorcontrib>Shui, Wenqing</creatorcontrib><creatorcontrib>Li, Shanshan</creatorcontrib><creatorcontrib>Korde, Anisha</creatorcontrib><creatorcontrib>Laprairie, Robert B</creatorcontrib><creatorcontrib>Stahl, Edward L</creatorcontrib><creatorcontrib>Ho, Jo-Hao</creatorcontrib><creatorcontrib>Zvonok, Nikolai</creatorcontrib><creatorcontrib>Zhou, Han</creatorcontrib><creatorcontrib>Kufareva, Irina</creatorcontrib><creatorcontrib>Wu, Beili</creatorcontrib><creatorcontrib>Zhao, Qiang</creatorcontrib><creatorcontrib>Hanson, Michael A</creatorcontrib><creatorcontrib>Bohn, Laura M</creatorcontrib><creatorcontrib>Makriyannis, Alexandros</creatorcontrib><creatorcontrib>Stevens, Raymond C</creatorcontrib><creatorcontrib>Liu, Zhi-Jie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hua, Tian</au><au>Vemuri, Kiran</au><au>Pu, Mengchen</au><au>Qu, Lu</au><au>Han, Gye Won</au><au>Wu, Yiran</au><au>Zhao, Suwen</au><au>Shui, Wenqing</au><au>Li, Shanshan</au><au>Korde, Anisha</au><au>Laprairie, Robert B</au><au>Stahl, Edward L</au><au>Ho, Jo-Hao</au><au>Zvonok, Nikolai</au><au>Zhou, Han</au><au>Kufareva, Irina</au><au>Wu, Beili</au><au>Zhao, Qiang</au><au>Hanson, Michael A</au><au>Bohn, Laura M</au><au>Makriyannis, Alexandros</au><au>Stevens, Raymond C</au><au>Liu, Zhi-Jie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crystal Structure of the Human Cannabinoid Receptor CB 1</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2016-10-20</date><risdate>2016</risdate><volume>167</volume><issue>3</issue><spage>750</spage><pages>750-</pages><eissn>1097-4172</eissn><abstract>Cannabinoid receptor 1 (CB
) is the principal target of Δ
-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB
is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB
in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB
-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB
ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB
and provides new opportunities for the design of next-generation CB
-targeting pharmaceuticals.</abstract><cop>United States</cop><pmid>27768894</pmid><doi>10.1016/j.cell.2016.10.004</doi></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 1097-4172 |
| ispartof | Cell, 2016-10, Vol.167 (3), p.750 |
| issn | 1097-4172 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Binding Sites Cannabinoid Receptor Antagonists - chemistry Cannabinoids - pharmacology Cannabis - chemistry Crystallography, X-Ray Dronabinol - pharmacology Endocannabinoids - pharmacology Humans Ligands Morpholines - chemical synthesis Morpholines - chemistry Protein Binding Protein Conformation, alpha-Helical Pyrazoles - chemical synthesis Pyrazoles - chemistry Receptor, Cannabinoid, CB1 - antagonists & inhibitors Receptor, Cannabinoid, CB1 - chemistry |
| title | Crystal Structure of the Human Cannabinoid Receptor CB 1 |
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