4rg2

Tudor Domain of Tumor suppressor p53BP1 with small molecule ligand

spinqualitylabelsall models 4rg2, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4rg2 is a 2 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 1.5Å Ligands: 3OO, EDO, UNX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease TP53B_HUMAN Note=A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;15)(q33;q22) with PDGFRB creating a TP53BP1-PDGFRB fusion protein. Function TP53B_HUMAN Plays a key role in the response to DNA damage. May have a role in checkpoint signaling during mitosis. Enhances TP53-mediated transcriptional activation. Publication Abstract from PubMed Improving our understanding of the role of chromatin regulators in the initiation, development, and suppression of cancer and other devastating diseases is critical, as they are integral players in regulating DNA integrity and gene expression. Developing small molecule inhibitors for this target class with cellular activity is a crucial step toward elucidating their specific functions. We specifically targeted the DNA damage response protein, 53BP1, which uses its tandem tudor domain to recognize histone H4 dimethylated on lysine 20 (H4K20me2), a modification related to double-strand DNA breaks. Through a cross-screening approach, we identified UNC2170 (1) as a micromolar ligand of 53BP1, which demonstrates at least 17-fold selectivity for 53BP1 as compared to other methyl-lysine (Kme) binding proteins tested. Structural studies revealed that the tert-butyl amine of UNC2170 anchors the compound in the methyl-lysine (Kme) binding pocket of 53BP1, making it competitive with endogenous Kme substrates. X-ray crystallography also demonstrated that UNC2170 binds at the interface of two tudor domains of a 53BP1 dimer. Importantly, this compound functions as a 53BP1 antagonist in cellular lysates and shows cellular activity by suppressing class switch recombination, a process which requires a functional 53BP1 tudor domain. These results demonstrate that UNC2170 is a functionally active, fragment-like ligand for 53BP1. Identification of a fragment-like small molecule ligand for the methyl-lysine binding protein, 53BP1.,Perfetti MT, Baughman BM, Dickson BM, Mu Y, Cui G, Mader P, Dong A, Norris JL, Rothbart SB, Strahl BD, Brown PJ, Janzen WP, Arrowsmith CH, Mer G, McBride KM, James LI, Frye SV ACS Chem Biol. 2015 Apr 17;10(4):1072-81. doi: 10.1021/cb500956g. Epub 2015 Jan, 28. PMID:25590533 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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