In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors by Cain, R, Brem, J, Zollman, D, McDonough, M, Johnson, R, Spencer, J, Makena, A, Abboud, M, Cahill, S, Lee, S, McHugh, P, Schofield, C, Fishwick, C

“…The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1 and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. …”

Identification of the KDM2/7 histone lysine demethylase subfamily inhibitor and its antiproliferative activity. by Suzuki, T, Ozasa, H, Itoh, Y, Zhan, P, Sawada, H, Mino, K, Walport, L, Ohkubo, R, Kawamura, A, Yonezawa, M, Tsukada, Y, Tumber, A, Nakagawa, H, Hasegawa, M, Sasaki, R, Mizukami, T, Schofield, C, Miyata, N

“…While inhibitors of KDM4s did not show any effect on cancer cells tested, the KDM2/7-subfamily inhibitor 9 exerted antiproliferative activity, indicating the potential for KDM2/7 inhibitors as anticancer agents.…”

In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases by Betts, J, Phee, L, Abdul Momin, M, Umland, K, Brem, J, Schofield, C, Wareham, D

Determining the role of the human transient receptor potential subfamily A member 1 (hTRPA1) ion channel in pain sensation by Saward, BG

A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. by Kruidenier, L, Chung, C, Cheng, Z, Liddle, J, Che, K, Joberty, G, Bantscheff, M, Bountra, C, Bridges, A, Diallo, H, Eberhard, D, Hutchinson, S, Jones, E, Katso, R, Leveridge, M, Mander, P, Mosley, J, Ramirez-Molina, C, Rowland, P, Schofield, C, Sheppard, R, Smith, J, Swales, C, Tanner, R, Thomas, P

“…Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. …”

A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. by Kruidenier, L, Chung, C, Cheng, Z, Liddle, J, Che, K, Joberty, G, Bantscheff, M, Bountra, C, Bridges, A, Diallo, H, Eberhard, D, Hutchinson, S, Jones, E, Katso, R, Leveridge, M, Mander, P, Mosley, J, Ramirez-Molina, C, Rowland, P, Schofield, C, Sheppard, R, Smith, J, Swales, C, Tanner, R, Thomas, P

“…Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. …”

A potent and selective inhibitor of a histone demethylase by England, K

“…JmjC KDM inhibitors have been reported in the literature but there are few subfamily selective examples. The aim of the work described in this thesis was to design and synthesise potent and subfamily selective inhibitors of human JmjC KDMs for use as chemical probes.…”

Targeting histone lysine demethylases - Progress, challenges, and the future. by Thinnes, C, England, K, Kawamura, A, Chowdhury, R, Schofield, C, Hopkinson, R

“…In humans, N(ε)-methyllysine residue demethylation is catalysed by two distinct subfamilies of demethylases (KDMs), the flavin-dependent KDM1 subfamily and the 2-oxoglutarate- (2OG) dependent JmjC subfamily, which both employ oxidative mechanisms. …”

Biochemical and structural insights into FIH-catalysed hydroxylation of transient receptor potential ankyrin repeat domains by Saward, B, Leissing, T, Clifton, I, Tumber, A, Timperley, C, Hopkinson, R, Schofield, C

“…TRP subfamily vanilloid member 3 (TRPV3) is involved in skin maintenance. …”

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. …”

The 2-oxoglutarate-dependent oxygenase JMJD6 catalyses oxidation of lysine residues to give 5S-hydroxylysine residues. by Mantri, M, Loik, N, Hamed, R, Claridge, T, McCullagh, J, Schofield, C

“…The work suggests that more than one subfamily of lysyl hydroxylases has evolved and illustrates the importance of stereochemical assignments in proteomic analyses.…”

Inhibition of the histone lysine demethylase JMJD2A by ejection of structural Zn(II). by Sekirnik, R, Rose, N, Thalhammer, A, Seden, P, Mecinović, J, Schofield, C

“…JMJD2A, a 2-oxoglutarate dependent N(epsilon)-methyl lysine histone demethylase, is inhibited by disruption of its Zn-binding site by Zn-ejecting compounds including disulfiram and ebselen; this observation may enable the development of inhibitors selective for this subfamily of 2OG dependent oxygenases that do not rely on binding to the highly-conserved Fe(ii)-containing active site.…”

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.…”

Lysine-241 has a role in coupling 2OG turnover with substrate oxidation during KDM4-catalysed histone demethylation by Hancock, R, Abboud, M, Smart, T, Flashman, E, Kawamura, A, Schofield, C, Hopkinson, R

“…Lys-241 of the KDM4 subfamily is proposed to be important in oxygen binding by KDM4A. …”

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.…”

Investigations on small molecule inhibitors targeting the histone H3K4 tri-methyllysine binding PHD-finger of JmjC histone demethylases by Bhushan, B, Erdmann, A, Zhang, Y, Belle, R, Johannson, C, Oppermann, U, Hopkinson, R, Schofield, C, Kawamura, A

“…Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily. Further work is required to develop potent and selective PHD finger inhibitors.…”

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. …”

Role of the jelly-roll fold in substrate binding by 2-oxoglutarate oxygenases. by Aik, W, McDonough, M, Thalhammer, A, Chowdhury, R, Schofield, C

“…2-Oxoglutarate (2OG) and ferrous iron dependent oxygenases catalyze two-electron oxidations of a range of small and large molecule substrates, including proteins/peptides/amino acids, nucleic acids/bases, and lipids, as well as natural products including antibiotics and signaling molecules. 2OG oxygenases employ variations of a core double-stranded β-helix (DSBH; a.k.a. jelly-roll, cupin or jumonji C (JmjC)) fold to enable binding of Fe(II) and 2OG in a subfamily conserved manner. The topology of the DSBH limits regions directly involved in substrate binding: commonly the first, second and eighth strands, loops between the second/third and fourth/fifth DSBH strands, and the N-terminal and C-terminal regions are involved in primary substrate, co-substrate and cofactor binding. …”

Structural and mechanistic studies on γ-butyrobetaine hydroxylase. by Leung, I, Krojer, T, Kochan, G, Henry, L, von Delft, F, Claridge, T, Oppermann, U, McDonough, M, Schofield, C

“…Crystallographic and sequence analyses reveal that BBOX and trimethyllysine hydroxylase form a subfamily of 2OG oxygenases that dimerize using an N-terminal domain. …”