title: Small-molecule modulators of methyl-lysine binding for the CBX7 chromodomain.
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.
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors: Chunyan
authors: C
authors: Ren
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors: Keita
authors: K
authors: Morohashi
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors: Alexander N
authors: AN
authors: Plotnikov
authors: Brookhaven National Laboratory, National Synchrotron Light Source, Upton, NY 11973, USA.
authors: Jean
authors: J
authors: Jakoncic
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors: Steven G
authors: SG
authors: Smith
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors: Jiaojie
authors: J
authors: Li
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors: Lei
authors: L
authors: Zeng
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Department of Natural Sciences, Hostos Community College of CUNY, Bronx, NY 10451, USA.
authors: Yoel
authors: Y
authors: Rodriguez
authors: Brookhaven National Laboratory, National Synchrotron Light Source, Upton, NY 11973, USA.
authors: Vivian
authors: V
authors: Stojanoff
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors: Martin
authors: M
authors: Walsh
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA. Electronic address: ming-ming.zhou@mssm.edu.
authors: Ming-Ming
authors: MM
authors: Zhou
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D063150:Polycomb Repressive Complex 1 / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity; D013498:Suramin / Q000737:chemistry / Q000378:metabolism
chemical_list: C503627:CBX7 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D054852:Small Molecule Libraries; D013498:Suramin; D063150:Polycomb Repressive Complex 1; D016650:Fluorescein-5-isothiocyanate; D008239:Lysine