Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy
PROteolysis TArgeting Chimeras (PROTACs) offer a therapeutic modality for protein target engagement, exploiting the ubiquitin–proteasome system to achieve precise degradation of a protein of interest. Recent advancements in understanding the structural biology of the CRL4A E3 ligase complex, particu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2025-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/15/2/206 |
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| author | Serena Rosignoli Sara Giordani Maddalena Pacelli Giulia Guarguaglini Alessandro Paiardini |
| author_facet | Serena Rosignoli Sara Giordani Maddalena Pacelli Giulia Guarguaglini Alessandro Paiardini |
| author_sort | Serena Rosignoli |
| collection | DOAJ |
| description | PROteolysis TArgeting Chimeras (PROTACs) offer a therapeutic modality for protein target engagement, exploiting the ubiquitin–proteasome system to achieve precise degradation of a protein of interest. Recent advancements in understanding the structural biology of the CRL4A E3 ligase complex, particularly its recruitment of neo-substrates through the G-loop motif, have provided valuable insights into the optimization of PROTAC efficacy. This perspective delves into the molecular determinants governing PROTAC selectivity and degradation efficiency, with a specific focus on kinases showing distinct G-loop conformations. By employing computational approaches to predict ternary complexes, along with the identification of binding patterns, it is possible to address limitations posed by structural data scarcity, thereby enhancing rational design strategies. |
| format | Article |
| id | doaj-art-a5c6faf9d4544d298e6c23f3d972ea0c |
| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-a5c6faf9d4544d298e6c23f3d972ea0c2025-08-20T02:44:59ZengMDPI AGBiomolecules2218-273X2025-02-0115220610.3390/biom15020206Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs EfficacySerena Rosignoli0Sara Giordani1Maddalena Pacelli2Giulia Guarguaglini3Alessandro Paiardini4Centre for Regenerative Medicine “Stefano Ferrari”, Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of Rome, 00185 Rome, ItalyDepartment of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of Rome, 00185 Rome, ItalyInstitute of Molecular Biology and Pathology, National Research Council of Italy, c/o Department of Biology and Biotechnology, Sapienza University of Rome, 00185 Rome, ItalyDepartment of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of Rome, 00185 Rome, ItalyPROteolysis TArgeting Chimeras (PROTACs) offer a therapeutic modality for protein target engagement, exploiting the ubiquitin–proteasome system to achieve precise degradation of a protein of interest. Recent advancements in understanding the structural biology of the CRL4A E3 ligase complex, particularly its recruitment of neo-substrates through the G-loop motif, have provided valuable insights into the optimization of PROTAC efficacy. This perspective delves into the molecular determinants governing PROTAC selectivity and degradation efficiency, with a specific focus on kinases showing distinct G-loop conformations. By employing computational approaches to predict ternary complexes, along with the identification of binding patterns, it is possible to address limitations posed by structural data scarcity, thereby enhancing rational design strategies.https://www.mdpi.com/2218-273X/15/2/206PROTACskinasesE3 ligasesG-loop |
| spellingShingle | Serena Rosignoli Sara Giordani Maddalena Pacelli Giulia Guarguaglini Alessandro Paiardini Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy Biomolecules PROTACs kinases E3 ligases G-loop |
| title | Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy |
| title_full | Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy |
| title_fullStr | Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy |
| title_full_unstemmed | Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy |
| title_short | Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy |
| title_sort | unraveling the engagement of kinases to crbn through a shared structural motif to optimize protacs efficacy |
| topic | PROTACs kinases E3 ligases G-loop |
| url | https://www.mdpi.com/2218-273X/15/2/206 |
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