8g46

Cryo-EM structure of DDB1deltaB-DDA1-DCAF16-BRD4(BD2)-MMH2

spinqualitylabelsall models 8g46, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8g46 is a 4 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 2.2Å Ligands: YK3, 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 Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics(1-3). Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs(4-6). The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4(DCAF16) ligase to the second bromodomain of BRD4 (BRD4(BD2)). BRD4(BD2), in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 A cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4(BD2) have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16(Cys58) covalent modification. Systematic mutagenesis of both DCAF16 and BRD4(BD2) revealed that the loop conformation around BRD4(His437), rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology. Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.,Li YD, Ma MW, Hassan MM, Hunkeler M, Teng M, Puvar K, Lumpkin R, Sandoval B, Jin CY, Ficarro SB, Wang MY, Xu S, Groendyke BJ, Sigua LH, Tavares I, Zou C, Tsai JM, Park PMC, Yoon H, Majewski FC, Marto JA, Qi J, Nowak RP, Donovan KA, Slabicki M, Gray NS, Fischer ES, Ebert BL bioRxiv [Preprint]. 2023 Feb 15:2023.02.14.528208. doi: , 10.1101/2023.02.14.528208. PMID:36824856 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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