9e2u

Crystal structure of DDB1-CRBN-ALV1 complex bound to triple ZnF of Helios (IKZF2 ZF1-3)

spinqualitylabelsall models 9e2u, resolution 4.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9e2u is a 24 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: X-ray diffraction, Resolution 4.11Å Ligands: RN9, 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 Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4(CRBN) to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has been characterized, it does not fully explain substrate specificity. To explore the role of residues adjacent to this core motif, we constructed a comprehensive ZF reporter library of 9,097 reporters derived from 1,655 human ZF proteins and conducted a library-on-library screen with 29 glutarimide analogs to identify compounds that collectively degrade 38 ZF reporters. Cryo-electron microscopy and crystal structures of ZFs in complex with CRBN revealed the importance of interactions beyond the core ZF degron. We used systematic mutagenesis of ZFs and CRBN to identify modes of neosubstrate recruitment requiring distinct amino acids. Finally, we found subtle chemical variations in glutarimide analogs that alter target scope and selectivity, thus providing a roadmap for their rational design. Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation.,Slabicki M, Park J, Nowak RP, Roy Burman SS, Pellman J, Zou C, Razumkov H, Carreiro J, Rastogi S, Goldstein A, Nagiec MM, Donovan KA, Che J, Hunkeler M, Geng Q, Hsu CL, Lakshminarayan M, Shu C, Zon RL, Kozicka Z, Park PMC, Tsai JM, Yoon H, Jones LH, Sperling AS, Gray NS, Fischer ES, Ebert BL Mol Cell. 2025 Aug 21;85(16):3184-3201.e14. doi: 10.1016/j.molcel.2025.07.019. PMID:40845806 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA