Ribosomal oxygenases are structurally conserved from prokaryotes to humans. by Chowdhury, R, Sekirnik, R, Brissett, N, Krojer, T, Ho, C, Ng, S, Clifton, I, Ge, W, Kershaw, N, Fox, G, Muniz, JR, Vollmar, M, Phillips, C, Pilka, E, Kavanagh, K, von Delft, F, Oppermann, U, McDonough, M, Doherty, A, Schofield, C

“…Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. …”

Ribosomal oxygenases are structurally conserved from prokaryotes to humans. by Chowdhury, R, Sekirnik, R, Brissett, N, Krojer, T, Ho, C, Ng, S, Clifton, I, Ge, W, Kershaw, N, Fox, G, Muniz, JR, Vollmar, M, Phillips, C, Pilka, E, Kavanagh, K, von Delft, F, Oppermann, U, McDonough, M, Doherty, A, Schofield, C

“…Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. …”

Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. by Rose, N, Ng, S, Mecinović, J, Liénard, B, Bello, S, Sun, Z, McDonough, M, Oppermann, U, Schofield, C

“…Here we describe a variety of inhibitor scaffolds that inhibit the human 2-oxoglutarate-dependent JMJD2 subfamily of histone demethylases. Combined with structural data, these chemical starting points will be useful to generate small-molecule probes to analyze the physiological roles of these enzymes in epigenetic signaling.…”

Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. by Rose, N, Ng, S, Mecinović, J, Liénard, B, Bello, S, Sun, Z, McDonough, M, Oppermann, U, Schofield, C

“…Here we describe a variety of inhibitor scaffolds that inhibit the human 2-oxoglutarate-dependent JMJD2 subfamily of histone demethylases. Combined with structural data, these chemical starting points will be useful to generate small-molecule probes to analyze the physiological roles of these enzymes in epigenetic signaling.…”

A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases. by Luo, X, Liu, Y, Kubicek, S, Myllyharju, J, Tumber, A, Ng, S, Che, K, Podoll, J, Heightman, T, Oppermann, U, Schreiber, S, Wang, X

“…The inhibitor derives from a structure-based design and preferentially inhibits the subfamily of trimethyl lysine demethylases. Its methyl ester prodrug, methylstat, selectively inhibits Jumonji C domain-containing his-tone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics.…”

Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. by Rose, N, Woon, E, Kingham, G, King, O, Mecinović, J, Clifton, I, Ng, S, Talib-Hardy, J, Oppermann, U, McDonough, M, Schofield, C

“…Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. …”

Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. by Rose, N, Woon, E, Tumber, A, Walport, L, Chowdhury, R, Li, X, King, O, Lejeune, C, Ng, S, Krojer, T, Chan, M, Rydzik, A, Hopkinson, R, Che, K, Daniel, M, Strain-Damerell, C, Gileadi, C, Kochan, G, Leung, I, Dunford, J, Yeoh, K, Ratcliffe, P, Burgess-Brown, N, von Delft, F, Muller, S

“…Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.…”

Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. by Rose, N, Woon, E, Kingham, G, King, O, Mecinović, J, Clifton, I, Ng, S, Talib-Hardy, J, Oppermann, U, McDonough, M, Schofield, C

“…Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. …”

Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor by England, K, Tumber, A, Krojer, T, Scozzafava, G, Ng, S, Daniel, M, Szykowska, A, Che, K, von Delft, F, Burgess-Brown, N, Kawamura, A, Schofield, C, Brennan, P

“…A potent inhibitor of the JmjC histone lysine demethylase KDM2A (compound 35, pIC50 7.2) with excellent selectivity over representatives from other KDM subfamilies has been developed; the discovery that a triazolopyridine compound binds to the active site of JmjC KDMs was followed by optimisation of the triazole substituent for KDM2A inhibition and selectivity. …”

5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation by Hopkinson, R, Tumber, A, Yapp, C, Chowdhury, R, Aik, W, Che, K, Li, X, Kristensen, J, King, O, Chan, M, Yeoh, K, Choi, H, Walport, L, Thinnes, C, Bush, J, Lejeune, C, Rydzik, A, Rose, N, Bagg, E, McDonough, M, Krojer, T, Yue, W, Ng, S, Olsen, L, Brennan, P

“…The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. …”

Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. by Ng, S, Kavanagh, K, McDonough, M, Butler, D, Pilka, E, Lienard, B, Bray, J, Savitsky, P, Gileadi, O, von Delft, F, Rose, N, Offer, J, Scheinost, J, Borowski, T, Sundstrom, M, Schofield, C, Oppermann, U

“…The results suggest distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect the complexity of reversible histone methylation and its role in chromatin biology.…”