Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.
|Abstract||Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid. Many cases of RD are associated with mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial alpha-oxidation step in the degradation of phytenic acid in peroxisomes. We describe t ... [truncated at 450 characters in length]|
|Author||McDonough, Michael A; Kavanagh, Kathryn L; Butler, Danica; et al|
|Subject||Aspartic Acid Binding Sites Coenzyme A Crystallization Crystallography, X-Ray Cysteine Escherichia coli Ferrous Compounds Histidine Humans Ketoglutaric Acids Mixed Function Oxygenases Models, Molecular Mutation Peroxisomes Phytanic Acid Protein Binding Protein Structure, Secondary Recombinant Proteins Refsum Disease Structure-Activity Relationship Transfection metabolism genetics metabolism metabolism genetics metabolism metabolism metabolism chemistry genetics enzymology analogs and derivatives metabolism drug therapy enzymology|
The crystal structure of human geranylgeranyl pyrophosphate synthase reveals a novel hexameric arrangement and inhibitory product binding.
|Abstract||Modification of GTPases with isoprenoid molecules derived from geranylgeranyl pyrophosphate or farnesyl pyrophosphate is an essential requisite for cellular signaling pathways. The synthesis of these isoprenoids proceeds in mammals through the mevalonate pathway, and the final steps in the synthesis are catalyzed by the related enzymes farnesyl pyrophosphate synthase and geranylgeranyl pyrophosphate synthase. Both enzymes play crucial roles in ce ... [truncated at 450 characters in length]|
|Author||Kavanagh, Kathryn L; Dunford, James E; Bunkoczi, Gabor; et al|
|Subject||Crystallization Crystallography, X-Ray Dimerization Enzyme Inhibitors Feedback, Physiological Geranylgeranyl-Diphosphate Geranylgeranyltransferase Humans Kinetics Molecular Motor Proteins Protein Binding Protein Conformation antagonists and inhibitors chemistry chemistry|
Structure and substrate specificity of the Pim-1 kinase.
|Abstract||The Pim kinases are a family of three vertebrate protein serine/threonine kinases (Pim-1, -2, and -3) belonging to the CAMK (calmodulin-dependent protein kinase-related) group. Pim kinases are emerging as important mediators of cytokine signaling pathways in hematopoietic cells, and they contribute to the progression of certain leukemias and solid tumors. A number of cytoplasmic and nuclear proteins are phosphorylated by Pim kinases and may act a ... [truncated at 450 characters in length]|
|Author||Bullock, Alex N; Debreczeni, Judit; Amos, Ann L; et al|
|Subject||Amino Acid Motifs Arginine Binding Sites Biotinylation Calcium-Calmodulin-Dependent Protein Kinase Type 1 Calcium-Calmodulin-Dependent Protein Kinases Calorimetry Cell Nucleus Crystallography, X-Ray Cytoplasm Glycine Hematopoietic Stem Cells Humans Kinetics Models, Molecular Peptide Library Peptide Nucleic Acids Peptides Phosphorylation Protein Binding Protein Conformation Protein Isoforms Protein Structure, Tertiary Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-pim-1 Substrate Specificity chemistry metabolism metabolism metabolism chemistry metabolism chemistry chemistry metabolism physiology physiology metabolism physiology|
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|
Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity.
|Abstract||Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact w ... [truncated at 450 characters in length]|
|Author||Pogacic, Vanda; Bullock, Alex N; Fedorov, Oleg; et al|
|Subject||Animals Antineoplastic Agents Cell Line, Tumor Chemistry, Pharmaceutical Drug Design Enzyme Inhibitors Humans Inhibitory Concentration 50 Mice Models, Chemical Models, Molecular Protein Binding Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-pim-1 Pyridazines Structure-Activity Relationship pharmacology methods chemistry pharmacology antagonists and inhibitors antagonists and inhibitors chemistry|