4X3T

Crystal structure of chromobox homolog 7 (CBX7) chromodomain with MS37452

Summary for 4X3T

• Entry DOI: 10.2210/pdb4x3t/pdb
• Related: 4X3S 4X3U
• Descriptor: Chromobox protein homolog 7, 1-[4-(2,3-dimethoxybenzoyl)piperazin-1-yl]-2-(3-methylphenoxy)ethanone, ZINC ION, ... (5 entities in total)
• Functional Keywords: cbx7, chromodomain, ms37452, inhibitor, transcription
• Biological source: Mus musculus (Mouse)
• Cellular location: Nucleus : Q8VDS3
• Total number of polymer chains: 6
• Total formula weight: 49426.72

Authors

Ren, C.,Jakoncic, J.,Zhou, M.M. (deposition date: 2014-12-01, release date: 2015-03-04, Last modification date: 2024-02-28)

Primary citation

Ren, C.,Morohashi, K.,Plotnikov, A.N.,Jakoncic, J.,Smith, S.G.,Li, J.,Zeng, L.,Rodriguez, Y.,Stojanoff, V.,Walsh, M.,Zhou, M.M.
Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain.
Chem.Biol., 22:161-168, 2015

PubMed Abstract: Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes trimethylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report the discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound, MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. These small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.

PubMed: 25660273
DOI: 10.1016/j.chembiol.2014.11.021

Experimental method

X-RAY DIFFRACTION (2.14 Å)