Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain
| Autor: | Martin J. Walsh, Jean Jakoncic, Alexander N. Plotnikov, Jiaojie Li, Yoel Rodríguez, Chunyan Ren, Lei Zeng, Steven G. Smith, Ming-Ming Zhou, Keita Morohashi, Vivian Stojanoff |
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| Jazyk: | angličtina |
| Předmět: |
Static Electricity
Clinical Biochemistry Suramin Plasma protein binding Methylation Biochemistry Article Chromodomain Histones Small Molecule Libraries 03 medical and health sciences Methyllysine chemistry.chemical_compound 0302 clinical medicine Transcription (biology) Cell Line Tumor Drug Discovery Humans Epigenetics Binding site Molecular Biology Cyclin-Dependent Kinase Inhibitor p16 030304 developmental biology Polycomb Repressive Complex 1 Pharmacology 0303 health sciences Binding Sites biology Lysine General Medicine Protein Structure Tertiary 3. Good health Histone chemistry 030220 oncology & carcinogenesis biology.protein Molecular Medicine Fluorescein-5-isothiocyanate Protein Binding |
| Zdroj: | Chemistry & Biology. (2):161-168 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2014.11.021 |
| Popis: | SummaryChromobox 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. |
| Databáze: | OpenAIRE |
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