Abstract:
:The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation makes them a promising target for studying inhibitory molecules that can modify the degree of cell proliferation. The discovery of specific inhibitors of CDKs such as polyhydroxylated flavones has opened the way to investigation and design of antimitotic compounds. A novel flavone, (-)-cis-5,7-dihydroxyphenyl-8-[4-(3-hydroxy-1-methyl)piperidinyl] -4H-1-benzopyran-4-one hydrochloride hemihydrate (L868276), is a potent inhibitor of CDKs. A chlorinated form, flavopiridol, is currently in phase I clinical trials as a drug against breast tumors. We determined the crystal structure of a complex between CDK2 and L868276 at 2.33 angstroms resolution and refined to an Rfactor 20.3%. The aromatic portion of the inhibitor binds to the adenine-binding pocket of CDK2, and the position of the phenyl group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP complex structure. The analysis of the position of this phenyl ring not only explains the great differences of kinase inhibition among the flavonoid inhibitors but also explains the specificity of L868276 to inhibit CDK2 and CDC2.
journal_name
Proc Natl Acad Sci U S Aauthors
De Azevedo WF Jr,Mueller-Dieckmann HJ,Schulze-Gahmen U,Worland PJ,Sausville E,Kim SHdoi
10.1073/pnas.93.7.2735subject
Has Abstractpub_date
1996-04-02 00:00:00pages
2735-40issue
7eissn
0027-8424issn
1091-6490journal_volume
93pub_type
杂志文章abstract::The development of Drosophila requires the function of the CREB-binding protein, dCBP. In flies, dCBP serves as a coactivator for the transcription factors Cubitus interruptus, Dorsal, and Mad, and as a cosuppressor of Drosophila T cell factor. Current models propose that CBP, through its intrinsic and associated hist...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.052509799
更新日期:2002-03-05 00:00:00
abstract::We have previously proven that human macrophages can phagocytose porcine cells even in the absence of Ab or complement opsonization, indicating that macrophages present a pivotal immunological obstacle to xenotransplantation. A recent report indicates that the signal regulatory protein (SIRP)alpha is a critical immune...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0609661104
更新日期:2007-03-20 00:00:00
abstract::Class Ib Qa-2 molecules are expressed in tissue culture cells as approximately 40-kDa membrane-bound, glycophosphatidylinositol-linked antigens and as approximately 39-kDa soluble polypeptides. Recently, alternative splicing events which delete exon 5 from a portion of Qa-2 transcripts were demonstrated to give rise t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.91.5.1883
更新日期:1994-03-01 00:00:00
abstract::In preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placenta's role has been a focus. In this study, we tested the hypothesis that decidual defects are an important determinant of the placental phenotype. We isolated human endometrial stromal cells from no...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1706546114
更新日期:2017-10-03 00:00:00
abstract::Heterotrimeric G proteins relay extracellular cues from heptahelical transmembrane receptors to downstream effector molecules. Composed of an alpha subunit with intrinsic GTPase activity and a betagamma heterodimer, the trimeric complex dissociates upon receptor-mediated nucleotide exchange on the alpha subunit, enabl...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0801569105
更新日期:2008-04-29 00:00:00
abstract::We have screened a human DNA library using as probe a chimpanzee sequence that contains homology to the polymerase gene of the endogenous baboon virus. One set of overlapping clones spans about 20 kilobases and contains regions of DNA sequence homology to the gag p30, gag p15, and polymerase genes of Moloney murine le...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.79.15.4709
更新日期:1982-08-01 00:00:00
abstract::A cyclic hexapeptide, cyclo(Pro-Gly-Pro-Gly-Pro-Gly), has been synthesized; its solution conformations were examined by 220-MHz nuclear magnetic resonance spectroscopy. The solution structures have been deduced, and shown to vary as a function of solvent polarity. In addition, it has been found that this cyclic peptid...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.69.7.1825
更新日期:1972-07-01 00:00:00
abstract::Rat superior cervical sympathetic ganglion was used to begin studying the regulation of molecular components of the synapse. Ganglionic postsynaptic densities (PSDs)exhibited a thin, disc-shaped profile electron microscopically, comparable to that described for brain. Moreover, the presumptive ganglionic PSD protein (...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.23.8687
更新日期:1987-12-01 00:00:00
abstract::The multisubunit enzyme aspartate transcarbamylase consists of six copies of two types of polypeptide chains, catalytic (C) and regulatory (R). A complex formed by the partial dissociation of this enzyme has been isolated. This species, which has the structure C(6)R(4), is a likely intermediate in the stepwise dissoci...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.71.4.1351
更新日期:1974-04-01 00:00:00
abstract::We have initiated immunological and drug-binding studies on the tubulins from different higher plant species. Antibodies were raised against electrophoretically separated rose (Rosa sp.) tubulin alpha- and beta-subunits and characterized by immunoblot autoradiographic assays. Each IgG preparation bound to its antigen ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.5.1440
更新日期:1984-03-01 00:00:00
abstract::Lambdoid phages form clear plaques and show reduced ability to establish immunity in strains of Escherichia coli that lack adenylate cyclase or catabolite activator protein. The absence of the activator protein or cyclic AMP reduces the frequency of lysogenization, but does not prevent steady-state repressor synthesis...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.69.2.366
更新日期:1972-02-01 00:00:00
abstract::A defined, minimal medium for the cellular slime mold Dictyostelium discoideum is reported. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.74.5.2157
更新日期:1977-05-01 00:00:00
abstract::Accurate protein folding is essential for proper cellular and organismal function. In the cell, protein folding is carefully regulated; changes in folding homeostasis (proteostasis) can disrupt many cellular processes and have been implicated in various neurodegenerative diseases and other pathologies. For many protei...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1610272113
更新日期:2016-11-22 00:00:00
abstract::The effects of messages initiated by one receptor on the covalent modification of a second receptor were studied by use of a technique for rapidly separating the receptors. Methylation of the bacterial-chemotactic serine receptor increases as a result of aspartate binding to the aspartate receptor. The aspartate-induc...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.85.22.8425
更新日期:1988-11-01 00:00:00
abstract::Serotonin (5-HT) controls a wide range of biological functions. In the brain, its implication as a neurotransmitter and in the control of behavioral traits has been largely documented. At the periphery, its modulatory role in physiological processes, such as the cardiovascular function, is still poorly understood. The...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.2233056100
更新日期:2003-11-11 00:00:00
abstract::Comparative genetic maps of Papuan Saccharum officinarum L. (2n = 80) and S. robustum (2n = 80) were constructed by using single-dose DNA markers (SDMs). SDM-framework maps of S. officinarum and S. robustum were compared with genetic maps of sorghum and maize by way of anchor restriction fragment length polymorphism p...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.94.26.14261
更新日期:1997-12-23 00:00:00
abstract::A close study of the metabolic regulation of hexose transport in a hamster fibroblast mutant, highly defective in the enzyme phosphoglucose isomerase (PGI mutant), reveals the requirement for at least three vectors for transport regulation. The downward regulation of the hexose transport system, called the "transport ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.4.1126
更新日期:1984-02-01 00:00:00
abstract::Animals capable of regenerating multiple tissue types, organs, and appendages after injury are common yet sporadic and include some sponge, hydra, planarian, and salamander (i.e., newt and axolotl) species, but notably such regenerative capacity is rare in mammals. The adult MRL mouse strain is a rare exception to the...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1000830107
更新日期:2010-03-30 00:00:00
abstract::The excess proton in water, H(+)(aq), plays a fundamental role in aqueous solution chemistry. Its solution thermodynamic properties are essential to molecular descriptions of that chemistry and for validation of dynamical calculations. Within the quasichemical theory of solutions those thermodynamic properties are con...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2005-05-10 00:00:00
abstract::The four core histones (H2A, H2B, H3, and H4) and DNA were assembled into nucleosome-like particles at physiological ionic strengths either by an extract of chromatin rich in nicking-closing activity or by the purified nicking-closing enzyme itself. When histone-DNA complexes were assembled in vitro from relaxed circu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.76.8.3779
更新日期:1979-08-01 00:00:00
abstract::A tetramer of the Mu transposase (MuA) pairs the recombination sites, cleaves the donor DNA, and joins these ends to a target DNA by strand transfer. Juxtaposition of the recombination sites is accomplished by the assembly of a stable synaptic complex of MuA protein and Mu DNA. This initial critical step is facilitate...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.93.3.1146
更新日期:1996-02-06 00:00:00
abstract::Appropriate hematopoietic stem cell (HSC) self-renewal reflects the tight regulation of cell cycle entry and lineage commitment. Here, we show that Id1, a dominant-negative regulator of E protein transcription factors, maintains HSC self-renewal by preserving the undifferentiated state. Id1-deficient HSCs show increas...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0607894104
更新日期:2007-01-23 00:00:00
abstract::Previous reconstructions of marine fishing fleets have aggregated data without regard to the artisanal and industrial sectors. Engine power has often been estimated from subsets of the developed world, leading to inflated results. We disaggregated data into three sectors, artisanal (unpowered/powered) and industrial, ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 历史文章,杂志文章
doi:10.1073/pnas.1820344116
更新日期:2019-06-18 00:00:00
abstract::Canonical Wnt signaling plays an important role in development and disease, regulating transcription of target genes and stabilizing many proteins phosphorylated by glycogen synthase kinase 3 (GSK3). We observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF (micropthalmia-asso...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1424576112
更新日期:2015-02-03 00:00:00
abstract::Once-abundant aerial insectivores, such as the Tree Swallow (Tachycineta bicolor), have declined steadily in the past several decades, making it imperative to understand all aspects of their ecology. Aerial insectivores forage on a mixture of aquatic and terrestrial insects that differ in fatty acid composition, speci...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1603998113
更新日期:2016-09-27 00:00:00
abstract::The signature of mass-independent fractionation of quadruple sulfur stable isotopes (S-MIF) in Archean rocks, ice cores, and Martian meteorites provides a unique probe of the oxygen and sulfur cycles in the terrestrial and Martian paleoatmospheres. Its mechanistic origin, however, contains some uncertainties. Even for...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1803420115
更新日期:2018-08-21 00:00:00
abstract::Selection is widely accepted as the principal force shaping phenotypic variation within populations. Its importance in speciation and macroevolution has been questioned, however, because phenotypic differences between species or higher taxa sometimes appear to be nonadaptive. Here, we use the quantitative trait locus ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.192360899
更新日期:2002-09-17 00:00:00
abstract::During an investigation of the role of ions in growth regulation, it was found that ethylene diamine tetraacetate (EDTA) inhibits DNA synthesis about 10-fold in cultures of chick embryo cells, while ethylene glycol bis(beta-amino ethyl ether)-N,N'-tetraacetate has no effect. RNA synthesis is only slightly inhibited by...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.69.3.712
更新日期:1972-03-01 00:00:00
abstract::Taz1 is a hybrid signal-transducing membrane receptor between Tar, an aspartate chemoreceptor, and EnvZ, an osmosensor of Escherichia coli that is able to induce ompC expression by phosphorylating OmpR (a transcriptional activator) in response to aspartate. When the Taz1 His-277, the proposed autophosphorylation site ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.24.11057
更新日期:1991-12-15 00:00:00
abstract::An oligomeric intermediate in the biosynthetic pathway of peptidoglycan was isolated from B. megaterium. The oligomer has been identified as [disaccharide(pentapeptide)]12 pyrophosphoryl undecaprenol. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.73.11.4200
更新日期:1976-11-01 00:00:00