Molecular glue CELMoD compounds are regulators of cereblon conformation
Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2022-11, Vol.378 (6619), p.549-553 |
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| container_title | Science (American Association for the Advancement of Science) |
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| creator | Watson, Edmond R Novick, Scott Matyskiela, Mary E Chamberlain, Philip P H de la Peña, Andres Zhu, Jinyi Tran, Eileen Griffin, Patrick R Wertz, Ingrid E Lander, Gabriel C |
| description | Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy. |
| doi_str_mv | 10.1126/science.add7574 |
| format | Article |
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Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.add7574</identifier><identifier>PMID: 36378961</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Adaptor Proteins, Signal Transducing - chemistry ; Allosteric properties ; Allosteric Regulation ; Biodegradation ; Cryoelectron Microscopy ; Degradation ; Drug development ; Protein Domains ; Protein structure ; Proteins ; Substrates ; Thalidomide - chemistry ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - chemistry</subject><ispartof>Science (American Association for the Advancement of Science), 2022-11, Vol.378 (6619), p.549-553</ispartof><rights>Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.</description><subject>Adaptor Proteins, Signal Transducing - chemistry</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation</subject><subject>Biodegradation</subject><subject>Cryoelectron Microscopy</subject><subject>Degradation</subject><subject>Drug development</subject><subject>Protein Domains</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Substrates</subject><subject>Thalidomide - chemistry</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitin-Protein Ligases - chemistry</subject><issn>0036-8075</issn><issn>1095-9203</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkb1PwzAQxS0EouVjZkORWFhC7bixkwUJlfIhFbHAbNmXc0mV2MVOkPjvSUWpgOmG97une_cIOWP0irFMTCLU6ACvdFXJXE73yJjRMk_LjPJ9MqaUi7SgMh-RoxhXlA5ayQ_JiAsui1KwMbl_8g1C3-iQLJsek9l88eRvE_Dt2veuiokOmARcDkTnQ0y8TQADmsa7AXLWh1Z3tXcn5MDqJuLpdh6T17v5y-whXTzfP85uFilMM9altqhMCcKYPM8qCVM0FpEiE4UBW3DItLYGJBUgNMrSCpFVAnIjmNWiBOTH5Prbd92bFitA1wXdqHWoWx0-lde1-qu4-k0t_YcqJZvmmRgMLrcGwb_3GDvV1hGwabRD30eVSS4ZG_60QS_-oSvfBzfE21Cs4IwzNlCTbwqCjzGg3R3DqNqUpLYlqW1Jw8b57ww7_qcV_gXAdZJX</recordid><startdate>20221104</startdate><enddate>20221104</enddate><creator>Watson, Edmond R</creator><creator>Novick, Scott</creator><creator>Matyskiela, Mary E</creator><creator>Chamberlain, Philip P</creator><creator>H de la Peña, Andres</creator><creator>Zhu, Jinyi</creator><creator>Tran, Eileen</creator><creator>Griffin, Patrick R</creator><creator>Wertz, Ingrid E</creator><creator>Lander, Gabriel C</creator><general>The American Association for the Advancement of Science</general><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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7756-4099</orcidid><orcidid>https://orcid.org/0000-0003-0213-3897</orcidid><orcidid>https://orcid.org/0000-0003-4921-1135</orcidid><orcidid>https://orcid.org/0000-0001-5436-4262</orcidid><orcidid>https://orcid.org/0000-0002-3404-690X</orcidid><orcidid>https://orcid.org/0000-0002-2368-6944</orcidid></search><sort><creationdate>20221104</creationdate><title>Molecular glue CELMoD compounds are regulators of cereblon conformation</title><author>Watson, Edmond R ; Novick, Scott ; Matyskiela, Mary E ; Chamberlain, Philip P ; H de la Peña, Andres ; Zhu, Jinyi ; Tran, Eileen ; Griffin, Patrick R ; Wertz, Ingrid E ; Lander, Gabriel C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-f8db9c6bb552d7c4ebfee0e168bcf83c2aafbc706c6ae79f662d6c5b61fa69ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adaptor Proteins, Signal Transducing - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Watson, Edmond R</au><au>Novick, Scott</au><au>Matyskiela, Mary E</au><au>Chamberlain, Philip P</au><au>H de la Peña, Andres</au><au>Zhu, Jinyi</au><au>Tran, Eileen</au><au>Griffin, Patrick R</au><au>Wertz, Ingrid E</au><au>Lander, Gabriel C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular glue CELMoD compounds are regulators of cereblon conformation</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2022-11-04</date><risdate>2022</risdate><volume>378</volume><issue>6619</issue><spage>549</spage><epage>553</epage><pages>549-553</pages><issn>0036-8075</issn><issn>1095-9203</issn><eissn>1095-9203</eissn><abstract>Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>36378961</pmid><doi>10.1126/science.add7574</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0001-7756-4099</orcidid><orcidid>https://orcid.org/0000-0003-0213-3897</orcidid><orcidid>https://orcid.org/0000-0003-4921-1135</orcidid><orcidid>https://orcid.org/0000-0001-5436-4262</orcidid><orcidid>https://orcid.org/0000-0002-3404-690X</orcidid><orcidid>https://orcid.org/0000-0002-2368-6944</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - chemistry Allosteric properties Allosteric Regulation Biodegradation Cryoelectron Microscopy Degradation Drug development Protein Domains Protein structure Proteins Substrates Thalidomide - chemistry Ubiquitin-protein ligase Ubiquitin-Protein Ligases - chemistry |
| title | Molecular glue CELMoD compounds are regulators of cereblon conformation |
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