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https://www.readbyqxmd.com/read/27214403/structural-analysis-of-human-kdm5b-guides-histone-demethylase-inhibitor-development
#1
Catrine Johansson, Srikannathasan Velupillai, Anthony Tumber, Aleksandra Szykowska, Edward S Hookway, Radoslaw P Nowak, Claire Strain-Damerell, Carina Gileadi, Martin Philpott, Nicola Burgess-Brown, Na Wu, Jola Kopec, Andrea Nuzzi, Holger Steuber, Ursula Egner, Volker Badock, Shonagh Munro, Nicholas B LaThangue, Sue Westaway, Jack Brown, Nick Athanasou, Rab Prinjha, Paul E Brennan, Udo Oppermann
Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families...
July 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/26759175/inhibition-of-kdm6-activity-during-murine-esc-differentiation-induces-dna-damage
#2
Christine Hofstetter, Justyna M Kampka, Sascha Huppertz, Heike Weber, Andreas Schlosser, Albrecht M Müller, Matthias Becker
Pluripotent embryonic stem cells (ESCs) are characterised by their capacity to self-renew indefinitely while maintaining the potential to differentiate into all cell types of an adult organism. Both the undifferentiated and differentiated states are defined by specific gene expression programs that are regulated at the chromatin level. Here, we have analysed the contribution of the H3K27me2- and H3K27me23-specific demethylases KDM6A and KDM6B to murine ESC differentiation by employing the GSK-J4 inhibitor, which is specific for KDM6 proteins, and by targeted gene knockout (KO) and knockdown...
February 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/26741168/8-substituted-pyrido-3-4-d-pyrimidin-4-3h-one-derivatives-as-potent-cell-permeable-kdm4-jmjd2-and-kdm5-jarid1-histone-lysine-demethylase-inhibitors
#3
Vassilios Bavetsias, Rachel M Lanigan, Gian Filippo Ruda, Butrus Atrash, Mark G McLaughlin, Anthony Tumber, N Yi Mok, Yann-Vaï Le Bihan, Sally Dempster, Katherine J Boxall, Fiona Jeganathan, Stephanie B Hatch, Pavel Savitsky, Srikannathasan Velupillai, Tobias Krojer, Katherine S England, Jimmy Sejberg, Ching Thai, Adam Donovan, Akos Pal, Giuseppe Scozzafava, James M Bennett, Akane Kawamura, Catrine Johansson, Aleksandra Szykowska, Carina Gileadi, Nicola A Burgess-Brown, Frank von Delft, Udo Oppermann, Zoe Walters, Janet Shipley, Florence I Raynaud, Susan M Westaway, Rab K Prinjha, Oleg Fedorov, Rosemary Burke, Christopher J Schofield, Isaac M Westwood, Chas Bountra, Susanne Müller, Rob L M van Montfort, Paul E Brennan, Julian Blagg
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay...
February 25, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26645689/characterization-of-a-linked-jumonji-domain-of-the-kdm5-jarid1-family-of-histone-h3-lysine-4-demethylases
#4
John R Horton, Amanda Engstrom, Elizabeth L Zoeller, Xu Liu, John R Shanks, Xing Zhang, Margaret A Johns, Paula M Vertino, Haian Fu, Xiaodong Cheng
The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases remove methyl groups from tri- and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC)...
February 5, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26263556/transcriptomic-profiling-and-h3k27me3-distribution-reveal-both-demethylase-dependent-and-independent-regulation-of-developmental-gene-transcription-in-cell-differentiation
#5
Sung Chul Kang, Se Kye Kim, Jin Choul Chai, Sun Hwa Kim, Kyoung-Jae Won, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
The removal of histone H3 trimethylation at lysine residue 27 (H3K27me3) plays a critical role in the transcriptional initiation of developmental genes. The H3K27me3-specific KDM6 demethylases JMJD3 and UTX are responsible for the transcriptional initiation of various developmental genes, but some genes are expressed in a KDM6 demethylase-independent manner. To address the role of H3K27me3 in the retinoic acid (RA)-induced differentiation of the human carcinoma NCCIT cell line, we inhibited JMJD3 and UTX using the H3K27me3 demethylase inhibitor GSK-J4...
2015: PloS One
https://www.readbyqxmd.com/read/26059336/expansion-and-functional-divergence-of-jumonji-c-containing-histone-demethylases-significance-of-duplications-in-ancestral-angiosperms-and-vertebrates
#6
Shengzhan Qian, Yingxiang Wang, Hong Ma, Liangsheng Zhang
Histone modifications, such as methylation and demethylation, are crucial mechanisms altering chromatin structure and gene expression. Recent biochemical and molecular studies have uncovered a group of histone demethylases called Jumonji C (JmjC) domain proteins. However, their evolutionary history and patterns have not been examined systematically. Here, we report extensive analyses of eukaryotic JmjC genes and define 14 subfamilies, including the Lysine-Specific Demethylase3 (KDM3), KDM5, JMJD6, Putative-Lysine-Specific Demethylase11 (PKDM11), and PKDM13 subfamilies, shared by plants, animals, and fungi...
August 2015: Plant Physiology
https://www.readbyqxmd.com/read/25279927/kruidenier-et-al-reply
#7
LETTER
Laurens Kruidenier, Chun-wa Chung, Zhongjun Cheng, John Liddle, KaHing Che, Gerard Joberty, Marcus Bantscheff, Chas Bountra, Angela Bridges, Hawa Diallo, Dirk Eberhard, Sue Hutchinson, Emma Jones, Roy Katso, Melanie Leveridge, Palwinder K Mander, Julie Mosley, Cesar Ramirez-Molina, Paul Rowland, Christopher J Schofield, Robert J Sheppard, Julia E Smith, Catherine Swales, Robert Tanner, Pamela Thomas, Anthony Tumber, Gerard Drewes, Udo Oppermann, Dinshaw J Patel, Kevin Lee, David M Wilson
No abstract text is available yet for this article.
October 2, 2014: Nature
https://www.readbyqxmd.com/read/25279926/inhibition-of-demethylases-by-gsk-j1-j4
#8
LETTER
Bo Heinemann, Jesper Morten Nielsen, Heidi Rye Hudlebusch, Michael J Lees, Dorthe Vang Larsen, Thomas Boesen, Marc Labelle, Lars-Ole Gerlach, Peter Birk, Kristian Helin
No abstract text is available yet for this article.
October 2, 2014: Nature
https://www.readbyqxmd.com/read/25101834/kdm6-demethylase-independent-loss-of-histone-h3-lysine-27-trimethylation-during-early-embryonic-development
#9
Karl B Shpargel, Joshua Starmer, Della Yee, Michael Pohlers, Terry Magnuson
The early mammalian embryo utilizes histone H3 lysine 27 trimethylation (H3K27me3) to maintain essential developmental genes in a repressive chromatin state. As differentiation progresses, H3K27me3 is removed in a distinct fashion to activate lineage specific patterns of developmental gene expression. These rapid changes in early embryonic chromatin environment are thought to be dependent on H3K27 demethylases. We have taken a mouse genetics approach to remove activity of both H3K27 demethylases of the Kdm6 gene family, Utx (Kdm6a, X-linked gene) and Jmjd3 (Kdm6b, autosomal gene)...
August 2014: PLoS Genetics
https://www.readbyqxmd.com/read/22986503/a-new-horizon-for-epigenetic-medicine
#10
Shuzhen Chen, Yang Shi
Histone lysine demethylases are chromatin modifiers that play important roles in many pathological processes such as inflammation and cancer, making them potentially attractive drug targets. In a recent study, Kruidenier et al. provided proof of concept by identifying chemical matters that inhibit demethylation mediated by the two related histone H3 lysine 27 demethylases, KDM6A and 6B (UTX and JMJD3). The KDM6 inhibitor shows remarkable substrate selectivity and can inhibit transcription of a plethora of pro-inflammatory genes in cell culture by altering H3K27me3 level at some of the KDM6 target genes...
March 2013: Cell Research
https://www.readbyqxmd.com/read/22842901/a-selective-jumonji-h3k27-demethylase-inhibitor-modulates-the-proinflammatory-macrophage-response
#11
Laurens Kruidenier, Chun-wa Chung, Zhongjun Cheng, John Liddle, KaHing Che, Gerard Joberty, Marcus Bantscheff, Chas Bountra, Angela Bridges, Hawa Diallo, Dirk Eberhard, Sue Hutchinson, Emma Jones, Roy Katso, Melanie Leveridge, Palwinder K Mander, Julie Mosley, Cesar Ramirez-Molina, Paul Rowland, Christopher J Schofield, Robert J Sheppard, Julia E Smith, Catherine Swales, Robert Tanner, Pamela Thomas, Anthony Tumber, Gerard Drewes, Udo Oppermann, Dinshaw J Patel, Kevin Lee, David M Wilson
The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease...
August 16, 2012: Nature
https://www.readbyqxmd.com/read/22002947/structural-basis-for-histone-h3-lys-27-demethylation-by-utx-kdm6a
#12
Toru Sengoku, Shigeyuki Yokoyama
Tri- and dimethylations of histone H3K9 (H3K9me3/2) and H3K27 (H3K27me3/2), both situated in the "A-R-Kme-S" sequence motif, mediate transcriptional repression of distinct genomic regions. H3K9me3/2 mainly governs constitutive heterochromatin formation, while H3K27me3/2 represses key developmental genes. The mechanisms by which histone-modifying enzymes selectively regulate the methylation states of H3K9 and H3K27 are poorly understood. Here we report the crystal structures of the catalytic fragment of UTX/KDM6A, an H3K27me3/2-specific demethylase, in the free and H3 peptide-bound forms...
November 1, 2011: Genes & Development
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