8X7G | pdb_00008x7g

Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation.

(2025) Nat Struct Mol Biol 32: 1825-1837

• PubMed: 40295770 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41594-025-01537-1
• Primary Citation of Related Structures:  
  8X7G, 8X7H


• PubMed Abstract: 
  

  Proteolysis targeting chimeras (PROTACs) hijack E3 ligases and the ubiquitin-proteasome system to achieve selective degradation of neo-substrates. Their ability to target otherwise intractable substrates has rendered them a valuable modality in drug discovery. However, only a handful of over 600 human E3 ligases have been functionalized for PROTAC applications. Here we show that the E3 ligase GID4 (glucose-induced degradation deficient complex 4) can be leveraged for targeted protein degradation using a noncovalent small molecule. We design and synthesize GID4-based PROTACs, exemplified by NEP162, which can eliminate endogenous BRD4 in a GID4- and ubiquitin-proteasome system-dependent manner. NEP162 exhibits antiproliferative activity and inhibits tumor growth in a xenograft model, hinting toward potential anticancer applications. We further present the crystal structures of GID4-PROTAC-BRD4 ternary complexes in three distinct states, unveiling plastic interactions between GID4 and BRD4. These structural insights, combined with in vitro and in vivo data, decipher the molecular basis by which the hereby developed PROTACs recruit BRD4 to GID4 for targeted degradation and expand our arsenal of PROTAC-exploitable E3 ligases.

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Organizational Affiliation: 
• Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China.
Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
Department of Ophthalmology, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK 'Belt and Road' Ophthalmology Joint Laboratory, Tianjin Medical University General Hospital, Tianjin, China. songboxie@tmu.edu.cn.
Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China. chendongxing@tmu.edu.cn.
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China. shilei@tmu.edu.cn.
Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China. dongcheng@tmu.edu.cn.
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