Research Interests:
Research Interests:
Research Interests:
Research Interests:
... phosphodiesterase 5 Michael Russwurm 1# , Christine Schlicker 2,3# , Michael Weyand 4 , Doris Koesling 1 , Clemens Steegborn 2,4* ... Circ Res 2007;100:309-327. 4. Jeon YH, Heo YS, Kim CM, Hyun YL, Lee TG, Ro S, Cho JM.... more
... phosphodiesterase 5 Michael Russwurm 1# , Christine Schlicker 2,3# , Michael Weyand 4 , Doris Koesling 1 , Clemens Steegborn 2,4* ... Circ Res 2007;100:309-327. 4. Jeon YH, Heo YS, Kim CM, Hyun YL, Lee TG, Ro S, Cho JM. Phosphodiesterase: ...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia possess seven Sirtuin isoforms, Sirt1-7, which differ in their subcellular localization and in the substrate proteins... more
Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia possess seven Sirtuin isoforms, Sirt1-7, which differ in their subcellular localization and in the substrate proteins they deacetylate. The physiological roles of Sirtuins and their potential use as therapeutic targets for metabolic and aging-related diseases have spurred interest in the development of small-molecule Sirtuin modulators. Here, we describe an approach exploiting the structures available for four human Sirtuins for the development of isoform-specific inhibitors. Virtual docking of a compound library into the peptide binding pockets of crystal structures of Sirt2, 3, 5 and 6 yielded compounds potentially discriminating between these isoforms. Further characterization in activity assays revealed several inhibitory compounds with little isoform specificity, but also two compounds with micromolar potency and high specificity for Sirt2. Structure compariso...
Research Interests:
Local levels of active thyroid hormone (3,3',5-triiodothyronine) are controlled by the action of activating and inactivating iodothyronine deiodinase enzymes. Deiodinases are selenocysteine-dependent membrane proteins catalyzing the... more
Local levels of active thyroid hormone (3,3',5-triiodothyronine) are controlled by the action of activating and inactivating iodothyronine deiodinase enzymes. Deiodinases are selenocysteine-dependent membrane proteins catalyzing the reductive elimination of iodide from iodothyronines through a poorly understood mechanism. We solved the crystal structure of the catalytic domain of mouse deiodinase 3 (Dio3), which reveals a close structural similarity to atypical 2-Cys peroxiredoxin(s) (Prx). The structure suggests a route for proton transfer to the substrate during deiodination and a Prx-related mechanism for subsequent recycling of the transiently oxidized enzyme. The proposed mechanism is supported by biochemical experiments and is consistent with the effects of mutations of conserved amino acids on Dio3 activity. Thioredoxin and glutaredoxin reduce the oxidized Dio3 at physiological concentrations, and dimerization appears to activate the enzyme by displacing an autoinhibitory...
Research Interests:
Research Interests:
Research Interests:
Research Interests: Biochemistry, Molecular Biology, Carbon Dioxide, Biology, Medicine, and 15 moreMolecular, Crystal structure, Sequence alignment, Cryptococcus Neoformans, Candida albicans, Enzyme, Natural Environment, Active site, Carbonic anhydrase, Protein Secondary Structure Prediction, Fungus, Amino Acid Sequence, Biochemistry and cell biology, Adenylyl Cyclase, and Molecular Sequence Data
Research Interests: Biochemistry, Molecular Biology, Biology, Mitochondria, Medicine, and 15 moreMolecular, Metabolic regulation, Glutamate, Humans, Animals, Cytochrome C, Enzyme, Acetylation, Enzyme activity, Citric Acid, Glutamate Dehydrogenase, Biochemistry and cell biology, Mitochondrial intermembrane space, Mitochondrial Proteins, and Nicotinamide adenine dinucleotide
Research Interests: Chemistry, Molecular Biology, Catalysis, Kinetics, Biology, and 15 moreCyanobacteria, Medicine, Manganese, Molecular, Mutation, Phosphatase, Escherichia coli, Hydrogen Bonding, Isoenzymes, Amino Acid Sequence, Hydrolysis, Biochemistry and cell biology, Molecular Sequence Data, DNA mutational analysis, and binding sites
Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Enzyme Inhibitors, Medicine, and 12 moreCell line, Humans, Animals, Stereochemistry, Medicinal, Structure activity Relationship, Protein Binding, Chelating Agents, Binding Site, Molecular Structure, Adenylyl Cyclase, and Pharmacology and pharmaceutical sciences
Research Interests:
The Ca2+ binding properties of C2 domains are essential for the function of their host proteins. We present here the first crystal structures showing an unexpected Ca2+ binding mode of the C2B domain of rabphilin-3A in atomic detail.... more
The Ca2+ binding properties of C2 domains are essential for the function of their host proteins. We present here the first crystal structures showing an unexpected Ca2+ binding mode of the C2B domain of rabphilin-3A in atomic detail. Acidic residues from the linker region between the C2A and C2B domains of rabphilin-3A interact with the Ca2+-binding region of the C2B domain. Because of these interactions, the coordination sphere of the two bound Ca2+ ions is almost complete. Mutation of these acidic residues to alanine resulted in a 10-fold decrease in the intrinsic Ca2+ binding affinity of the C2B domain. Using NMR spectroscopy, we show that this interaction occurred only in the Ca2+-bound state of the C2B domain. In addition, this Ca2+ binding mode was maintained in the C2 domain tandem fragment. In NMR-based liposome binding assays, the linker was not released upon phospholipid binding. Therefore, this unprecedented Ca2+ binding mode not only shows how a C2 domain increases its i...
Research Interests:
The reaction of LScBr2 (1), LYI2 (3), LHoI2 (4), or LErI2 (5) [L = N,N′′‐(1,3‐dimethyl‐1,3‐propanediylidene)bis(N′,N′‐diethyl‐1,2‐ethanediamine)] with Me3SnF was investigated. Treatment of 1 with Me3SnF results in the formation of... more
The reaction of LScBr2 (1), LYI2 (3), LHoI2 (4), or LErI2 (5) [L = N,N′′‐(1,3‐dimethyl‐1,3‐propanediylidene)bis(N′,N′‐diethyl‐1,2‐ethanediamine)] with Me3SnF was investigated. Treatment of 1 with Me3SnF results in the formation of (Me3BrSn‐μ‐F)2LSc (2) while compounds 3−5 give [LSnMe2][Me3SnI2] (6) as the only product that could be isolated and characterized. Metathesis reactions of 1 with AgSO3CF3 led to LSc(SO3CF3)2 (7). Compounds 1, 2, 6 and 7 were characterized by single‐crystal X‐ray structural analysis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)