5EPK

Crystal Structure of chromodomain of CBX2 in complex with inhibitor UNC3866

Summary for 5EPK

• Entry DOI: 10.2210/pdb5epk/pdb
• Related: 5EPJ 5EPL
• Related PRD ID: PRD_002208
• Descriptor: Chromobox protein homolog 2, unc3866, UNKNOWN ATOM OR ION, ... (4 entities in total)
• Functional Keywords: structural genomics, structural genomics consortium, sgc, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 7363.62

Authors

Liu, Y.,Tempel, W.,Walker, J.R.,Stuckey, J.I.,Dickson, B.M.,James, L.I.,Frye, S.V.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Min, J.,Structural Genomics Consortium (SGC) (deposition date: 2015-11-11, release date: 2015-12-23, Last modification date: 2025-04-02)

Primary citation

Stuckey, J.I.,Dickson, B.M.,Cheng, N.,Liu, Y.,Norris, J.L.,Cholensky, S.H.,Tempel, W.,Qin, S.,Huber, K.G.,Sagum, C.,Black, K.,Li, F.,Huang, X.P.,Roth, B.L.,Baughman, B.M.,Senisterra, G.,Pattenden, S.G.,Vedadi, M.,Brown, P.J.,Bedford, M.T.,Min, J.,Arrowsmith, C.H.,James, L.I.,Frye, S.V.
A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1.
Nat.Chem.Biol., 12:180-187, 2016

PubMed Abstract: We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a K(d) of ∼100 nM for each, and is 6- to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects.

PubMed: 26807715
DOI: 10.1038/nchembio.2007

Experimental method

X-RAY DIFFRACTION (1.8 Å)