Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design.
|Abstract||Glutamine synthetase (GS) catalyzes the ligation of glutamate and ammonia to form glutamine, with concomitant hydrolysis of ATP. In mammals, the activity eliminates cytotoxic ammonia, at the same time converting neurotoxic glutamate to harmless glutamine; there are a number of links between changes in GS activity and neurodegenerative disorders, such as Alzheimer's disease. In plants, because of its importance in the assimilation and re-assimilat ... [truncated at 450 characters in length]|
|Author||Krajewski, Wojciech W; Collins, Ruairi; Holmberg-Schiavone, Lovisa; et al|
|Subject||Adenosine Triphosphate Amino Acid Sequence Animals Apoenzymes Binding Sites Catalytic Domain Cloning, Molecular Crystallography, X-Ray Dogs Drug Design Drug Interactions Glutamate-Ammonia Ligase Herbicides Humans Hydrogen Bonding Kinetics Ligands Magnesium Models, Chemical Models, Molecular Molecular Sequence Data Pharmaceutical Preparations Protein Binding Protein Conformation Protein Structure, Tertiary Sequence Homology, Amino Acid Substrate Specificity Temperature metabolism pharmacology chemistry chemistry genetics isolation and purification metabolism chemical synthesis chemistry metabolism pharmacology chemical synthesis chemistry|
Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases.
|Abstract||The dynamic methylation of histone lysyl residues plays an important role in biology by regulating transcription, maintaining genomic integrity, and by contributing to epigenetic effects. 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 t ... [truncated at 450 characters in length]|
|Author||Rose, Nathan R; Ng, Stanley S; Mecinović, Jasmin; et al|
|Subject||Crystallography, X-Ray Dose-Response Relationship, Drug Enzyme Inhibitors Humans Ketoglutaric Acids Models, Molecular Molecular Structure Oxidoreductases, N-Demethylating Protein Structure, Tertiary Stereoisomerism Structure-Activity Relationship pharmacology chemical synthesis chemistry pharmacology antagonists and inhibitors metabolism|
Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches.
|Abstract||Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N(epsilon)-methylated lysine residues in histones. 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. The results of initial binding and inhibition assays directed the production an ... [truncated at 450 characters in length]|
|Author||Rose, Nathan R; Woon, Esther C Y; Kingham, Guy L; et al|
|Subject||Binding Sites Binding, Competitive Combinatorial Chemistry Techniques Crystallography, X-Ray Humans Jumonji Domain-Containing Histone Demethylases Models, Molecular Oxalic Acids Spectrometry, Mass, Electrospray Ionization Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Structure-Activity Relationship Tyrosine antagonists and inhibitors chemistry chemical synthesis chemistry analogs and derivatives chemical synthesis chemistry|
Selective inhibition of BET bromodomains.
|Abstract||Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of ... [truncated at 450 characters in length]|
|Author||Filippakopoulos, Panagis; Qi, Jun; Picaud, Sarah; et al|
|Subject||Amino Acid Sequence Animals Azirines Binding Sites Carcinoma, Squamous Cell Cell Differentiation Cell Line, Tumor Cell Proliferation Chromatin Dihydropyridines Female Humans Mice Mice, Nude Models, Molecular Molecular Sequence Data Nuclear Proteins Protein Binding Protein Structure, Tertiary Recombinant Proteins Sequence Alignment Skin Neoplasms Stereoisomerism Transcription Factors chemical synthesis chemistry pharmacology physiopathology drug effects drug effects metabolism chemical synthesis chemistry pharmacology antagonists and inhibitors metabolism drug effects metabolism physiopathology antagonists and inhibitors metabolism|
New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights.
|Abstract||Protein kinase casein kinase 2 (CK2) is a serine/threonine kinase with evidence of implication in growth dysregulation and apoptosis resistance, making it a relevant target for cancer therapy. Several CK2 inhibitors have been developed showing variable efficiency, emphasizing the need to expand the chemical diversity of those inhibitors. We report the identification and characterization of 2,8-difurandicarboxylic acid derivatives as a new class o ... [truncated at 450 characters in length]|
|Author||López-Ramos, Miriam; Prudent, Renaud; Moucadel, Virginie; et al|
|Subject||Animals Binding Sites Casein Kinase II Cell Line, Tumor Crystallography, X-Ray Enzyme Activation Enzyme Inhibitors Enzyme Stability Humans Proto-Oncogene Proteins c-pim-1 antagonists and inhibitors chemistry drug effects chemical synthesis chemistry pharmacology antagonists and inhibitors chemistry|