9saf

Ternary PROTAC-mediated complex of BRD4-BD1/CRBN/DDB1 and JQ1-AcQ bifunctional degrader

spinqualitylabelsall models 9saf, resolution 2.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9saf is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.55Å Ligands: A1JM8, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DDB1_HUMAN Required for DNA repair. Binds to DDB2 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). May also play a role in ubiquitination of CDKN1B/p27kip when associated with CUL4 and SKP2. Publication Abstract from PubMed Targeted protein degradation with compounds like proteolysis targeting chimeras (PROTACs) directs disease-associated proteins to the E3 ligase ubiquitin-proteasome system for removal. However, commonly employed E3 ligases such as cereblon (CRBN) are broadly expressed. To metabolically gate PROTAC activity, we developed an enzymatic activation strategy by integrating an O-GlcNAc modification to the cyclimids, ligands derived from the natural motifs recognized by CRBN. These sugar-coated PROTACs (SCPs) were designed using structural analyses of representative cyclimid degraders complexed with CRBN and target protein BRD4. We found that glycosylation of the cyclimid reduced CRBN binding and complex formation with BRD4 until enzymatic removal of the O-GlcNAc moiety by O-GlcNAcase (OGA). The requirement for enzymatic activation is demonstrated by in vitro biochemical binding, cellular degradation, and cell viability assays in engineered and native cell lines. O-GlcNAc is thus an effective mechanism to gate targeted protein degradation modalities that motivates the development of similar strategies to enhance selectivity with other protein modifications. Enzyme-Activated Sugar-Coated Bifunctional Degraders.,Zhu Q, Fischer G, Cheng SS, Payne NC, Peter D, Mody AC, Arce-Solano S, Shen D, Lin Z, Mazitschek R, Kessler D, Woo CM J Am Chem Soc. 2025 Sep 24;147(38):34672-34680. doi: 10.1021/jacs.5c09843. Epub , 2025 Sep 12. PMID:40937862 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA