4RG2

Tudor Domain of Tumor suppressor p53BP1 with small molecule ligand

Summary for 4RG2

• Entry DOI: 10.2210/pdb4rg2/pdb
• Descriptor: Tumor suppressor p53-binding protein 1, 3-bromo-N-[3-(tert-butylamino)propyl]benzamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: 53bp1 tudor, structural genomics, structural genomics consortium, sgc, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q12888
• Total number of polymer chains: 2
• Total formula weight: 28743.22

Authors

Dong, A.,Mader, P.,James, L.,Perfetti, M.,Tempel, W.,Frye, S.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Structural Genomics Consortium (SGC) (deposition date: 2014-09-29, release date: 2014-10-15, Last modification date: 2023-09-20)

Primary citation

Perfetti, M.T.,Baughman, B.M.,Dickson, B.M.,Mu, Y.,Cui, G.,Mader, P.,Dong, A.,Norris, J.L.,Rothbart, S.B.,Strahl, B.D.,Brown, P.J.,Janzen, W.P.,Arrowsmith, C.H.,Mer, G.,McBride, K.M.,James, L.I.,Frye, S.V.
Identification of a fragment-like small molecule ligand for the methyl-lysine binding protein, 53BP1.
ACS Chem. Biol., 10:1072-1081, 2015

PubMed Abstract: 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.

PubMed: 25590533
DOI: 10.1021/cb500956g

Experimental method

X-RAY DIFFRACTION (1.5 Å)