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  • 1
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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
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    The immunological evolution of catalysis (1996)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1996-02-23
    Description: The germline genes used by the mouse to generate the esterolytic antibody 48G7 were cloned and expressed in an effort to increase our understanding of the detailed molecular mechanisms by which the immune system evolves catalytic function. The nine replacement mutations that were fixed during affinity maturation increased affinity for the transition state analogue by a factor of 10(4), primarily the result of a decrease in the dissociation rate of the hapten-antibody complex. There was a corresponding increase in the rate of reaction of antibody with substrate, k(cat)/k(m), from 1.7 x 10(2)M(-1) min(-1) to 1.4 x 10(4)M(-1) min(-1). The three-dimensional crystal structure of the 48G7-transition state analogue complex at 2.0 angstroms resolution indicates that one of the nine residues in which somatic mutations have been fixed directly contact the hapten. Thus, in the case of 48G7, affinity maturation appears to play a conformational role, either in reorganizing the active site geometry of limiting side-chain and backbone flexibility of the germline antibody. The crystal structure and analysis of somatic and directed active site mutants underscore the role of transition state stabilization in the evolution of this catalytic antibody.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Patten, P A -- Gray, N S -- Yang, P L -- Marks, C B -- Wedemayer, G J -- Boniface, J J -- Stevens, R C -- Schultz, P G -- R01 AL24695/PHS HHS/ -- New York, N.Y. -- Science. 1996 Feb 23;271(5252):1086-91.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, CA 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8599084" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies, Catalytic/chemistry/genetics/*immunology/metabolism ; Antibody Affinity ; Antigen-Antibody Complex ; Antigen-Antibody Reactions ; Base Sequence ; Binding Sites ; Catalysis ; Cloning, Molecular ; Crystallization ; Crystallography, X-Ray ; *Evolution, Molecular ; Genes, Immunoglobulin ; Haptens/immunology ; Immunoglobulin Fab Fragments/genetics/immunology ; Immunoglobulin Heavy Chains/genetics/immunology ; Immunoglobulin Light Chains/genetics/immunology ; Mice ; Molecular Sequence Data ; Mutation ; Protein Conformation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
    Location Call Number Expected Availability
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    PAPER CURRENT
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