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  • Binding Sites  (119)
  • American Association for the Advancement of Science (AAAS)  (119)
  • 1995-1999  (110)
  • 1980-1984  (9)
  • 1940-1944
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  • American Association for the Advancement of Science (AAAS)  (119)
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  • 1
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    Peptide antagonists of the human estrogen receptor (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-07-31
    Description: Estrogen receptor alpha transcriptional activity is regulated by distinct conformational states that are the result of ligand binding. Phage display was used to identify peptides that interact specifically with either estradiol- or tamoxifen-activated estrogen receptor alpha. When these peptides were coexpressed with estrogen receptor alpha in cells, they functioned as ligand-specific antagonists, indicating that estradiol-agonist and tamoxifen-partial agonist activities do not occur by the same mechanism. The ability to regulate estrogen receptor alpha transcriptional activity by targeting sites outside of the ligand-binding pocket has implications for the development of estrogen receptor alpha antagonists for the treatment of tamoxifen-refractory breast cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Norris, J D -- Paige, L A -- Christensen, D J -- Chang, C Y -- Huacani, M R -- Fan, D -- Hamilton, P T -- Fowlkes, D M -- McDonnell, D P -- DK48807/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 1999 Jul 30;285(5428):744-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Duke University Medical Center, Department of Pharmacology and Cancer Biology, Durham, NC 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10426998" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Estradiol/metabolism/*pharmacology ; Estrogen Antagonists/*pharmacology ; Estrogen Receptor alpha ; Humans ; Ligands ; Mifepristone/pharmacology ; Molecular Sequence Data ; Peptide Library ; Peptides/metabolism/*pharmacology ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Estrogen/agonists/*antagonists & inhibitors/chemistry/*metabolism ; Recombinant Fusion Proteins/pharmacology ; Tamoxifen/metabolism/*pharmacology ; Transcription Factor AP-1/genetics/metabolism ; Transcription, Genetic/drug effects
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Receptor for motilin identified in the human gastrointestinal system (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-06-26
    Description: Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feighner, S D -- Tan, C P -- McKee, K K -- Palyha, O C -- Hreniuk, D L -- Pong, S S -- Austin, C P -- Figueroa, D -- MacNeil, D -- Cascieri, M A -- Nargund, R -- Bakshi, R -- Abramovitz, M -- Stocco, R -- Kargman, S -- O'Neill, G -- Van Der Ploeg, L H -- Evans, J -- Patchett, A A -- Smith, R G -- Howard, A D -- New York, N.Y. -- Science. 1999 Jun 25;284(5423):2184-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Disorders, Department of Medicinal Chemistry, Merck Research Laboratories, Building RY-80Y-265, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10381885" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Amino Acid Sequence ; Base Sequence ; Binding Sites ; Calcium/metabolism ; Cell Line ; Chromosome Mapping ; Chromosomes, Human, Pair 13 ; Cloning, Molecular ; Colon/*metabolism ; Erythromycin/metabolism ; GTP-Binding Proteins/metabolism ; Humans ; In Situ Hybridization ; Intestine, Small/*metabolism ; Ligands ; Molecular Sequence Data ; Motilin/analogs & derivatives/*metabolism ; Receptors, Gastrointestinal Hormone/*chemistry/*genetics/metabolism ; Receptors, Neuropeptide/*chemistry/*genetics/metabolism ; Stomach/*metabolism ; Thyroid Gland/metabolism ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Discovery of a small molecule insulin mimetic with antidiabetic activity in mice (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-05-13
    Description: Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, B -- Salituro, G -- Szalkowski, D -- Li, Z -- Zhang, Y -- Royo, I -- Vilella, D -- Diez, M T -- Pelaez, F -- Ruby, C -- Kendall, R L -- Mao, X -- Griffin, P -- Calaycay, J -- Zierath, J R -- Heck, J V -- Smith, R G -- Moller, D E -- New York, N.Y. -- Science. 1999 May 7;284(5416):974-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Endocrinology, Merck Research Laboratories, R80W250, Post Office Box 2000, Rahway, NJ 07065, USA. bei_zhang@merck.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10320380" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Ascomycota/*metabolism ; Binding Sites ; Blood Glucose/metabolism ; CHO Cells ; Cricetinae ; Diabetes Mellitus, Type 2/*drug therapy ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Enzyme Activation ; Glucose Tolerance Test ; Hyperglycemia/drug therapy ; Hypoglycemic Agents/chemistry/metabolism/*pharmacology/therapeutic use ; Indoles/chemistry/metabolism/*pharmacology/therapeutic use ; Insulin/blood/metabolism/*pharmacology ; Insulin Receptor Substrate Proteins ; Mice ; Mice, Mutant Strains ; Mice, Obese ; Molecular Mimicry ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Conformation/drug effects ; Receptor, Epidermal Growth Factor/metabolism ; Receptor, IGF Type 1/metabolism ; Receptor, Insulin/chemistry/*metabolism ; Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Structure of nitric oxide synthase oxygenase dimer with pterin and substrate (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-04-16
    Description: Crystal structures of the murine cytokine-inducible nitric oxide synthase oxygenase dimer with active-center water molecules, the substrate L-arginine (L-Arg), or product analog thiocitrulline reveal how dimerization, cofactor tetrahydrobiopterin, and L-Arg binding complete the catalytic center for synthesis of the essential biological signal and cytotoxin nitric oxide. Pterin binding refolds the central interface region, recruits new structural elements, creates a 30 angstrom deep active-center channel, and causes a 35 degrees helical tilt to expose a heme edge and the adjacent residue tryptophan-366 for likely reductase domain interactions and caveolin inhibition. Heme propionate interactions with pterin and L-Arg suggest that pterin has electronic influences on heme-bound oxygen. L-Arginine binds to glutamic acid-371 and stacks with heme in an otherwise hydrophobic pocket to aid activation of heme-bound oxygen by direct proton donation and thereby differentiate the two chemical steps of nitric oxide synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crane, B R -- Arvai, A S -- Ghosh, D K -- Wu, C -- Getzoff, E D -- Stuehr, D J -- Tainer, J A -- HL58883/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 1998 Mar 27;279(5359):2121-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9516116" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arginine/chemistry/*metabolism ; Binding Sites ; Biopterin/*analogs & derivatives/chemistry/metabolism ; Citrulline/analogs & derivatives/chemistry/metabolism ; Crystallography, X-Ray ; Dimerization ; Hydrogen Bonding ; Isoenzymes/chemistry/metabolism ; Ligands ; Macrophages/enzymology ; Mice ; Models, Molecular ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase/*chemistry/metabolism ; Nitric Oxide Synthase Type II ; *Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Thiourea/analogs & derivatives/chemistry/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    The structure of nitric oxide synthase oxygenase domain and inhibitor complexes (1997)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1997-10-23
    Description: The nitric oxide synthase oxygenase domain (NOSox) oxidizes arginine to synthesize the cellular signal and defensive cytotoxin nitric oxide (NO). Crystal structures determined for cytokine-inducible NOSox reveal an unusual fold and heme environment for stabilization of activated oxygen intermediates key for catalysis. A winged beta sheet engenders a curved alpha-beta domain resembling a baseball catcher's mitt with heme clasped in the palm. The location of exposed hydrophobic residues and the results of mutational analysis place the dimer interface adjacent to the heme-binding pocket. Juxtaposed hydrophobic O2- and polar L-arginine-binding sites occupied by imidazole and aminoguanidine, respectively, provide a template for designing dual-function inhibitors and imply substrate-assisted catalysis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crane, B R -- Arvai, A S -- Gachhui, R -- Wu, C -- Ghosh, D K -- Getzoff, E D -- Stuehr, D J -- Tainer, J A -- CA53914/CA/NCI NIH HHS/ -- HL58883/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 1997 Oct 17;278(5337):425-31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9334294" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arginine/chemistry/metabolism ; Binding Sites ; Biopterin/analogs & derivatives/metabolism ; *Caenorhabditis elegans Proteins ; Catalysis ; Crystallography, X-Ray ; Dimerization ; Enzyme Induction ; Enzyme Inhibitors/metabolism ; Guanidines/metabolism ; Heme/chemistry ; Homeodomain Proteins/chemistry/*genetics/physiology ; Hydrogen Bonding ; Imidazoles/metabolism ; Isoenzymes/antagonists & inhibitors/*chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Nitric Oxide Synthase/antagonists & inhibitors/*chemistry/metabolism ; Oxidation-Reduction ; Oxygen/metabolism ; Oxygenases/chemistry/metabolism ; *Protein Conformation ; Protein Folding ; Protein Structure, Secondary
    Print ISSN: 0036-8075
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  • 6
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    Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-07-03
    Description: Regulation of N-methyl-D-aspartate (NMDA) receptor activity by kinases and phosphatases contributes to the modulation of synaptic transmission. Targeting of these enzymes near the substrate is proposed to enhance phosphorylation-dependent modulation. Yotiao, an NMDA receptor-associated protein, bound the type I protein phosphatase (PP1) and the adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) holoenzyme. Anchored PP1 was active, limiting channel activity, whereas PKA activation overcame constitutive PP1 activity and conferred rapid enhancement of NMDA receptor currents. Hence, yotiao is a scaffold protein that physically attaches PP1 and PKA to NMDA receptors to regulate channel activity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Westphal, R S -- Tavalin, S J -- Lin, J W -- Alto, N M -- Fraser, I D -- Langeberg, L K -- Sheng, M -- Scott, J D -- F32 NS010202/NS/NINDS NIH HHS/ -- GM 48231/GM/NIGMS NIH HHS/ -- NS10202/NS/NINDS NIH HHS/ -- NS10543/NS/NINDS NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Jul 2;285(5424):93-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Vollum Institute, Oregon Health Sciences University, 3181 S.W. Sam Jackson Road, Portland, OR 97201, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10390370" target="_blank"〉PubMed〈/a〉
    Keywords: A Kinase Anchor Proteins ; *Adaptor Proteins, Signal Transducing ; Amino Acid Sequence ; Animals ; Binding Sites ; Carrier Proteins/*metabolism ; Cell Line ; Cyclic AMP/analogs & derivatives/pharmacology ; Cyclic AMP-Dependent Protein Kinases/*metabolism ; Cytoskeletal Proteins/*metabolism ; Enzyme Inhibitors/pharmacology ; Holoenzymes/metabolism ; Humans ; Molecular Sequence Data ; Okadaic Acid/pharmacology ; Patch-Clamp Techniques ; Peptide Fragments/pharmacology ; Phosphoprotein Phosphatases/*metabolism ; Phosphorylation ; Rats ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Recombinant Fusion Proteins/metabolism ; Signal Transduction ; Thionucleotides/pharmacology ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Recognition of the codon-anticodon helix by ribosomal RNA (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-09-11
    Description: Translational fidelity is established by ribosomal recognition of the codon-anticodon interaction within the aminoacyl-transfer RNA (tRNA) site (A site) of the ribosome. Experiments are presented that reveal possible contacts between 16S ribosomal RNA and the codon-anticodon complex. N1 methylation of adenine at position 1492 (A1492) and A1493 interfered with A-site tRNA binding. Mutation of A1492 and A1493 to guanine or cytosine also impaired A-site tRNA binding. The deleterious effects of A1492G or A1493G (or both) mutations were compensated by 2'fluorine substitutions in the mRNA codon. The results suggest that the ribosome recognizes the codon-anticodon complex by adenine contacts to the messenger RNA backbone and provide a mechanism for molecular discrimination of correct versus incorrect codon-anticodon pairs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshizawa, S -- Fourmy, D -- Puglisi, J D -- GM51266/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1999 Sep 10;285(5434):1722-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305-5126, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10481006" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/analogs & derivatives/metabolism ; Anticodon/chemistry/*metabolism ; Binding Sites ; Biotin ; Codon/chemistry/*metabolism ; Escherichia coli ; Hydrogen Bonding ; Methylation ; Mutagenesis, Site-Directed ; *Nucleic Acid Conformation ; Paromomycin/pharmacology ; Protein Biosynthesis ; RNA, Bacterial/chemistry/metabolism ; RNA, Ribosomal, 16S/chemistry/genetics/*metabolism ; RNA, Transfer, Met/metabolism ; RNA, Transfer, Phe/metabolism ; Ribosomes/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-10-26
    Description: Cerebral deposition of amyloid beta peptide (Abeta) is an early and critical feature of Alzheimer's disease. Abeta generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: beta-secretase and gamma-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of beta-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for beta-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vassar, R -- Bennett, B D -- Babu-Khan, S -- Kahn, S -- Mendiaz, E A -- Denis, P -- Teplow, D B -- Ross, S -- Amarante, P -- Loeloff, R -- Luo, Y -- Fisher, S -- Fuller, J -- Edenson, S -- Lile, J -- Jarosinski, M A -- Biere, A L -- Curran, E -- Burgess, T -- Louis, J C -- Collins, F -- Treanor, J -- Rogers, G -- Citron, M -- New York, N.Y. -- Science. 1999 Oct 22;286(5440):735-41.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Amgen, Inc., One Amgen Center Drive, M/S 29-2-B, Thousand Oaks, CA 91320-1799, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10531052" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/drug therapy/*enzymology ; Amino Acid Motifs ; Amino Acid Sequence ; Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides/*biosynthesis ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Aspartic Acid Endopeptidases/chemistry/genetics/*isolation & ; purification/*metabolism ; Binding Sites ; Brain/enzymology/metabolism ; Cell Line ; Cloning, Molecular ; Endopeptidases ; Endosomes/enzymology ; Gene Expression ; Gene Library ; Golgi Apparatus/enzymology ; Humans ; Hydrogen-Ion Concentration ; Molecular Sequence Data ; Oligonucleotides, Antisense/pharmacology ; Peptides/metabolism ; Protease Inhibitors/pharmacology ; RNA, Messenger/genetics/metabolism ; Recombinant Fusion Proteins/metabolism ; Transfection
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1 (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-09-25
    Description: Phosphorylation sites in members of the protein kinase A (PKA), PKG, and PKC kinase subfamily are conserved. Thus, the PKB kinase PDK1 may be responsible for the phosphorylation of PKC isotypes. PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. All members of the PKC family tested formed complexes with PDK1. PDK1-dependent phosphorylation of PKCdelta in vitro was stimulated by combined PKC and PDK1 activators. The activation loop phosphorylation of PKCdelta in response to serum stimulation of cells was PI 3-kinase-dependent and was enhanced by PDK1 coexpression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Le Good, J A -- Ziegler, W H -- Parekh, D B -- Alessi, D R -- Cohen, P -- Parker, P J -- New York, N.Y. -- Science. 1998 Sep 25;281(5385):2042-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Protein Phosphorylation Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9748166" target="_blank"〉PubMed〈/a〉
    Keywords: 3-Phosphoinositide-Dependent Protein Kinases ; Binding Sites ; Cell Line ; Chromones/pharmacology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Humans ; Isoenzymes/*metabolism ; Morpholines/pharmacology ; Phosphatidylcholines/pharmacology ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphatidylinositol Phosphates ; Phosphatidylserines/pharmacology ; Phosphorylation ; Protein Kinase C/*metabolism ; Protein Kinase C beta ; Protein-Serine-Threonine Kinases/*metabolism ; Recombinant Proteins/metabolism ; Tetradecanoylphorbol Acetate/pharmacology
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-07-24
    Description: Selective protein kinase inhibitors were developed on the basis of the unexpected binding mode of 2,6,9-trisubstituted purines to the adenosine triphosphate-binding site of the human cyclin-dependent kinase 2 (CDK2). By iterating chemical library synthesis and biological screening, potent inhibitors of the human CDK2-cyclin A kinase complex and of Saccharomyces cerevisiae Cdc28p were identified. The structural basis for the binding affinity and selectivity was determined by analysis of a three-dimensional crystal structure of a CDK2-inhibitor complex. The cellular effects of these compounds were characterized in mammalian cells and yeast. In the latter case the effects were characterized on a genome-wide scale by monitoring changes in messenger RNA levels in treated cells with high-density oligonucleotide probe arrays. Purine libraries could provide useful tools for analyzing a variety of signaling and regulatory pathways and may lead to the development of new therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gray, N S -- Wodicka, L -- Thunnissen, A M -- Norman, T C -- Kwon, S -- Espinoza, F H -- Morgan, D O -- Barnes, G -- LeClerc, S -- Meijer, L -- Kim, S H -- Lockhart, D J -- Schultz, P G -- New York, N.Y. -- Science. 1998 Jul 24;281(5376):533-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9677190" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/*analogs & derivatives/chemistry/metabolism/pharmacology ; Binding Sites ; *CDC2-CDC28 Kinases ; CDC28 Protein Kinase, S cerevisiae/antagonists & inhibitors ; Cell Division/drug effects ; Crystallography, X-Ray ; Cyclin A/metabolism ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinases/*antagonists & inhibitors ; Drug Evaluation, Preclinical ; Flavonoids/chemistry/metabolism/pharmacology ; Gene Expression Regulation, Fungal/drug effects ; Genes, Fungal ; Humans ; Hydrogen Bonding ; Oligonucleotide Probes ; Phosphates/metabolism ; Piperidines/chemistry/metabolism/pharmacology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Purines/chemical synthesis/chemistry/metabolism/*pharmacology ; RNA, Messenger/genetics/metabolism ; Saccharomyces cerevisiae/enzymology/genetics ; Structure-Activity Relationship ; Transcription, Genetic/drug effects ; Tumor Cells, Cultured
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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