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    Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase.
    BMC Biol 2016 08 9;14:65. Epub 2016 Aug 9.
    Medical Research Council Mitochondrial Biology Unit, Wellcome Trust / MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
    Background: The biguanides are a family of drugs with diverse clinical applications. Metformin, a widely used anti-hyperglycemic biguanide, suppresses mitochondrial respiration by inhibiting respiratory complex I. Phenformin, a related anti-hyperglycemic biguanide, also inhibits respiration, but proguanil, which is widely used for the prevention of malaria, does not. Read More

    The Mitochondrial Unfoldase-Peptidase Complex ClpXP Controls Bioenergetics Stress and Metastasis.
    PLoS Biol 2016 07 7;14(7):e1002507. Epub 2016 Jul 7.
    Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
    Mitochondria must buffer the risk of proteotoxic stress to preserve bioenergetics, but the role of these mechanisms in disease is poorly understood. Using a proteomics screen, we now show that the mitochondrial unfoldase-peptidase complex ClpXP associates with the oncoprotein survivin and the respiratory chain Complex II subunit succinate dehydrogenase B (SDHB) in mitochondria of tumor cells. Knockdown of ClpXP subunits ClpP or ClpX induces the accumulation of misfolded SDHB, impairing oxidative phosphorylation and ATP production while activating "stress" signals of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and autophagy. Read More

    Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle.
    PLoS Biol 2015 30;13(11):e1002306. Epub 2015 Nov 30.
    Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
    Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the "conformational selection and population shift" theory, ligand binding selects a particular conformation. Read More

    Mapping the Free Energy Landscape of PKA Inhibition and Activation: A Double-Conformational Selection Model for the Tandem cAMP-Binding Domains of PKA RIα.
    PLoS Biol 2015 30;13(11):e1002305. Epub 2015 Nov 30.
    Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
    Protein Kinase A (PKA) is the major receptor for the cyclic adenosine monophosphate (cAMP) secondary messenger in eukaryotes. cAMP binds to two tandem cAMP-binding domains (CBD-A and -B) within the regulatory subunit of PKA (R), unleashing the activity of the catalytic subunit (C). While CBD-A in RIα is required for PKA inhibition and activation, CBD-B functions as a "gatekeeper" domain that modulates the control exerted by CBD-A. Read More

    Single Turnover Autophosphorylation Cycle of the PKA RIIβ Holoenzyme.
    PLoS Biol 2015 Jul 9;13(7):e1002192. Epub 2015 Jul 9.
    Department of Pharmacology, University of California at San Diego, La Jolla, California, United States of America; Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, United States of America.
    To provide tight spatiotemporal signaling control, the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) holoenzyme typically nucleates a macromolecular complex or a "PKA signalosome." Using the RIIβ holoenzyme as a prototype, we show how autophosphorylation/dephosphorylation of the RIIβ subunit, as well as cAMP and metal ions, contribute to the dynamics of PKA signaling. While we showed previously that the RIIβ holoenzyme could undergo a single turnover autophosphorylation with adenosine triphosphate and magnesium (MgATP) and trap both products in the crystal lattice, we asked here whether calcium could trap an ATP:RIIβ holoenzyme since the RIIβ holoenzyme is located close to ion channels. Read More

    Structure-guided design of selective Epac1 and Epac2 agonists.
    PLoS Biol 2015 Jan 20;13(1):e1002038. Epub 2015 Jan 20.
    Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
    The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and in vivo. Read More

    Extracellular ATP hydrolysis inhibits synaptic transmission by increasing ph buffering in the synaptic cleft.
    PLoS Biol 2014 May 20;12(5):e1001864. Epub 2014 May 20.
    Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
    Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Read More

    Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.
    PLoS Biol 2014 Mar 25;12(3):e1001820. Epub 2014 Mar 25.
    Biozentrum, University of Basel, Basel, Switzerland.
    Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. Read More

    Deciphering the structural basis of eukaryotic protein kinase regulation.
    PLoS Biol 2013 Oct 15;11(10):e1001680. Epub 2013 Oct 15.
    Biomedical Sciences, University of California, San Diego, La Jolla, California, United States of America.
    Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Read More

    Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
    PLoS Biol 2013 Sep 10;11(9):e1001651. Epub 2013 Sep 10.
    Biophysical Sciences Institute, Durham University, Durham, United Kingdom ; Department of Chemistry, Durham University, Durham, United Kingdom.
    Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. Read More

    Protection of Sinorhizobium against host cysteine-rich antimicrobial peptides is critical for symbiosis.
    PLoS Biol 2011 Oct 4;9(10):e1001169. Epub 2011 Oct 4.
    School of Medicine & Dentistry, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
    Sinorhizobium meliloti differentiates into persisting, nitrogen-fixing bacteroids within root nodules of the legume Medicago truncatula. Nodule-specific cysteine-rich antimicrobial peptides (NCR AMPs) and the bacterial BacA protein are essential for bacteroid development. However, the bacterial factors central to the NCR AMP response and the in planta role of BacA are unknown. Read More

    Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance.
    PLoS Biol 2011 Jul 19;9(7):e1001105. Epub 2011 Jul 19.
    Department of Biological Chemistry, University of California, Irvine, California, United States of America.
    Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. Read More

    Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.
    PLoS Biol 2011 Apr 19;9(4):e1000612. Epub 2011 Apr 19.
    Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
    Mitochondrial shape is determined by fission and fusion reactions catalyzed by large GTPases of the dynamin family, mutation of which can cause neurological dysfunction. While fission-inducing protein phosphatases have been identified, the identity of opposing kinase signaling complexes has remained elusive. We report here that in both neurons and non-neuronal cells, cAMP elevation and expression of an outer-mitochondrial membrane (OMM) targeted form of the protein kinase A (PKA) catalytic subunit reshapes mitochondria into an interconnected network. Read More

    Synthesis of new chiral heterocyclic Schiff base modulated Cu(II)/Zn(II) complexes: their comparative binding studies with CT-DNA, mononucleotides and cleavage activity.
    J Photochem Photobiol B 2011 May 6;103(2):166-79. Epub 2011 Mar 6.
    Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India.
    New Schiff base ligand L derived from the condensation reaction of 2-amino-3-formylchromone with (R)-2-amino-2-phenylethanol was synthesized and characterized which involves combination element of ammine functionality and naturally occurring heterocyclic chromone, 4H-benzopyran-4-one. Subsequently, their complexes 1 and 2 with Cu(NO₃)₂ and Zn(NO₃)₂, respectively were prepared. The DNA binding studies of the ligand L and complexes 1 and 2 with CT-DNA as compared to classical anticancer drug cisplatin were carried out by employing different optical methods viz, UV-vis, fluorescence, circular dichroism and viscosity measurements. Read More

    Firefly luciferase inhibition.
    J Photochem Photobiol B 2010 Oct 3;101(1):1-8. Epub 2010 Jul 3.
    Centro de Investigação em Química (CIQ-UP), Grupo de Ciências Biológicas e Bioanalíticas, Faculdade de Farmácia da Universidade de Coimbra, Polo das Ciências da Saúde, 3000-548 Coimbra, Portugal.
    Firefly luciferase (Luc) is the most studied of the luciferase enzymes and the mechanism and kinetics of the reactions catalyzed by this enzyme have been relatively well characterized. Luc catalyzes the bioluminescent reaction involving firefly luciferin (D-LH(2)), adenosine triphosphate (ATP), magnesium ion and molecular oxygen with the formation of an electronically excited species (oxyluciferin), inorganic pyrophosphate (PPi), carbon dioxide and adenosine monophosphate (AMP). Luc also catalyzes other non-luminescent reactions, which can interfere with the light production mechanism. Read More

    Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.
    PLoS Biol 2010 Apr 13;8(4):e1000355. Epub 2010 Apr 13.
    Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, Valbonne, France.
    Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. Read More

    Tumor suppressor Fhit protein interacts with protoporphyrin IX in vitro and enhances the response of HeLa cells to photodynamic therapy.
    J Photochem Photobiol B 2007 Jan 20;86(1):35-42. Epub 2006 Sep 20.
    Department of Biotechnology, Division of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk, Poland.
    Fhit, the product of tumor suppressor fragile histidine triad (FHIT) gene, exhibits antitumor activity of still largely unknown cellular background. However, it is believed that Fhit-Ap(3)A or Fhit-AMP complex might act as a second class messenger in cellular signal transduction pathway involved in cell proliferation and apoptosis. We demonstrate here for the first time that the photosensitizer, protoporphyrin IX (which is a natural precursor of heme) binds to Fhit protein and its mutants in the active site in vitro. Read More

    A conserved mechanism for sulfonucleotide reduction.
    PLoS Biol 2005 Aug 19;3(8):e250. Epub 2005 Jul 19.
    Department of Chemistry, University of California, Berkeley, California, USA.
    Sulfonucleotide reductases are a diverse family of enzymes that catalyze the first committed step of reductive sulfur assimilation. In this reaction, activated sulfate in the context of adenosine-5'-phosphosulfate (APS) or 3'-phosphoadenosine 5'-phosphosulfate (PAPS) is converted to sulfite with reducing equivalents from thioredoxin. The sulfite generated in this reaction is utilized in bacteria and plants for the eventual production of essential biomolecules such as cysteine and coenzyme A. Read More

    Ras and Gpa2 mediate one branch of a redundant glucose signaling pathway in yeast.
    PLoS Biol 2004 May 11;2(5):E128. Epub 2004 May 11.
    Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
    Addition of glucose to starved yeast cells elicits a dramatic restructuring of the transcriptional and metabolic state of the cell. While many components of the signaling network responsible for this response have been identified, a comprehensive view of this network is lacking. We have used global analysis of gene expression to assess the roles of the small GTP-binding proteins, Ras2 and Gpa2, in mediating the transcriptional response to glucose. Read More

    Synthesis, photochemistry and application of (7-methoxycoumarin-4-yl)methyl-caged 8-bromoadenosine cyclic 3',5'-monophosphate and 8-bromoguanosine cyclic 3',5'-monophosphate photolyzed in the nanosecond time region.
    J Photochem Photobiol B 1999 Nov-Dec;53(1-3):91-102
    Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
    New caged derivatives of hydrolysis-resistant 8-bromoadenosine cyclic 3',5'-monophosphate (8-Br-cAMP) and 8-bromoguanosine cyclic 3',5'-monophosphate (8-Br-cGMP) are described. The compounds are the axial and equatorial isomers of the (7-methoxycoumarin-4-yl)methyl (MCM) esters of cyclic nucleotides. Synthesis is accomplished by treatment of 4-bromomethyl-7-methoxycoumarin with the tetra-n-butylammonium salts of the 8-bromo-substituted cyclic nucleotides or with the free acids of 8-Br-cAMP and 8-Br-cGMP in the presence of silver(I) oxide. Read More

    Novel caged compounds of hydrolysis-resistant 8-Br-cAMP and 8-Br-cGMP: photolabile NPE esters.
    J Photochem Photobiol B 1998 Jan;42(1):71-8
    Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
    The application of the 1-(2-nitrophenyl)ethyl (NPE) moiety as a photolabile ligand for the release of hydrolysis-resistant 8-Br-cAMP and 8-Br-cGMP was examined. NPE-caged 8-Br-cAMP and 8-Br-cGMP liberate 8-Br-cAMP and 8-Br-cGMP during irradiation with ultraviolet light. The synthesis procedure resulted in diastereoisomeric mixtures, which were chromatographically separated into the axial and equatorial isomers of NPE-caged 8-Br-cAMP and 8-Br-cGMP. Read More

    Characterization of the reactive intermediates in laser flash photolysis of adenine, adenosine and dAMP using acetone as photosensitizer.
    J Photochem Photobiol B 1995 Apr;28(1):65-70
    Laboratory of Radiation Chemistry, Shanghai Institute of Nuclear Research, People's Republic of China.
    Transient absorption spectra of adenine, adenosine and 2'-deoxyadenosine 5'-monophosphate (dAMP) arising from 248 nm laser flash photolysis using acetone as a photosensitizer have been observed. The intermediates recorded are assigned to the excited triplet states and dehydrogenated radicals of adenine and its nucleoside and nucleotide. The excited triplet states of adenine and its derivatives are produced via triplet-triplet excitation transfer and observed for the first time, while the dehydrogenated radicals stemming from the interaction of triplet acetone with adenine and its derivatives via electron transfer through a five-member-ring electron donor-acceptor intermediate. Read More

    Phototransduction: different mechanisms in vertebrates and invertebrates.
    J Photochem Photobiol B 1990 Nov;7(2-4):107-48
    Institut für Biologie II, RWTH Aachen, F.R.G.
    The photoreceptor cells of invertebrate animals differ from those of vertebrates in morphology and physiology. Our present knowledge of the different structures and transduction mechanisms of the two animal groups is described. In invertebrates, rhodopsin is converted by light into a meta-rhodopsin which is thermally stable and is usually re-isomerized by light. Read More

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