8u4u

Crystal structure of 53BP1 tandem Tudor domain homodimer engineered with two disulfide bridges

spinqualitylabelsall models 8u4u, resolution 3.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8u4u is a 10 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 3.79Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The recruitment of 53BP1 to chromatin, mediated by its recognition of histone H4 dimethylated at lysine 20 (H4K20me2), is important for DNA double-strand break repair. Using a series of small molecule antagonists, we demonstrate a conformational equilibrium between an open and a pre-existing lowly populated closed state of 53BP1 in which the H4K20me2 binding surface is buried at the interface between two interacting 53BP1 molecules. In cells, these antagonists inhibit the chromatin recruitment of wild type 53BP1, but do not affect 53BP1 variants unable to access the closed conformation despite preservation of the H4K20me2 binding site. Thus, this inhibition operates by shifting the conformational equilibrium toward the closed state. Our work therefore identifies an auto-associated form of 53BP1-autoinhibited for chromatin binding-that can be stabilized by small molecule ligands encapsulated between two 53BP1 protomers. Such ligands are valuable research tools to study the function of 53BP1 and have the potential to facilitate the development of new drugs for cancer therapy. An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering.,Cui G, Botuyan MV, Drane P, Hu Q, Bragantini B, Thompson JR, Schuller DJ, Detappe A, Perfetti MT, James LI, Frye SV, Chowdhury D, Mer G Nat Commun. 2023 Sep 29;14(1):6091. doi: 10.1038/s41467-023-41821-6. PMID:37773238 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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