Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase.

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.

authors

De Azevedo WF Jr,Mueller-Dieckmann HJ,Schulze-Gahmen U,Worland PJ,Sausville E,Kim SH

doi

10.1073/pnas.93.7.2735

subject

Has Abstract

pub_date

1996-04-02 00:00:00

pages

2735-40

issue

7

eissn

0027-8424

issn

1091-6490

journal_volume

93

pub_type

杂志文章
  • The interaction between the coactivator dCBP and Modulo, a chromatin-associated factor, affects segmentation and melanotic tumor formation in Drosophila.

    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

    authors: Bantignies F,Goodman RH,Smolik SM

    更新日期:2002-03-05 00:00:00

  • Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages.

    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

    authors: Ide K,Wang H,Tahara H,Liu J,Wang X,Asahara T,Sykes M,Yang YG,Ohdan H

    更新日期:2007-03-20 00:00:00

  • Alternative splicing of class Ib major histocompatibility complex transcripts in vivo leads to the expression of soluble Qa-2 molecules in murine blood.

    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

    authors: Tabaczewski P,Shirwan H,Lewis K,Stroynowski I

    更新日期:1994-03-01 00:00:00

  • Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.

    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

    authors: Garrido-Gomez T,Dominguez F,Quiñonero A,Diaz-Gimeno P,Kapidzic M,Gormley M,Ona K,Padilla-Iserte P,McMaster M,Genbacev O,Perales A,Fisher SJ,Simón C

    更新日期:2017-10-03 00:00:00

  • Molecular architecture of Galphao and the structural basis for RGS16-mediated deactivation.

    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

    authors: Slep KC,Kercher MA,Wieland T,Chen CK,Simon MI,Sigler PB

    更新日期:2008-04-29 00:00:00

  • Cloned endogenous retroviral sequences from human DNA.

    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

    authors: Bonner TI,O'Connell C,Cohen M

    更新日期:1982-08-01 00:00:00

  • Conformational interconversions of the cyclic hexapeptide cyclo(Pro-Gly) 3 .

    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

    authors: Deber CM,Torchia DA,Wong SC,Blout ER

    更新日期:1972-07-01 00:00:00

  • Regulation of molecular components of the synapse in the developing and adult rat superior cervical ganglion.

    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

    authors: Wu K,Black IB

    更新日期:1987-12-01 00:00:00

  • An intermediate complex in the dissociation of aspartate transcarbamylase.

    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

    authors: Evans DR,Pastra-Landis SC,Lipscomb WN

    更新日期:1974-04-01 00:00:00

  • Tubulins from different higher plant species are immunologically nonidentical and bind colchicine differentially.

    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

    authors: Morejohn LC,Bureau TE,Tocchi LP,Fosket DE

    更新日期:1984-03-01 00:00:00

  • Establishment of repression by lambdoid phage in catabolite activator protein and adenylate cyclase mutants of Escherichia coli.

    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

    authors: Grodzicker T,Arditti RR,Eisen H

    更新日期:1972-02-01 00:00:00

  • A defined minimal medium for axenic strains of Dictyostelium discoideum.

    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

    authors: Franke J,Kessin R

    更新日期:1977-05-01 00:00:00

  • Quantitative determination of ribosome nascent chain stability.

    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

    authors: Samelson AJ,Jensen MK,Soto RA,Cate JH,Marqusee S

    更新日期:2016-11-22 00:00:00

  • Receptor interactions through phosphorylation and methylation pathways in bacterial chemotaxis.

    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

    authors: Sanders DA,Koshland DE Jr

    更新日期:1988-11-01 00:00:00

  • Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function.

    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

    authors: Côté F,Thévenot E,Fligny C,Fromes Y,Darmon M,Ripoche MA,Bayard E,Hanoun N,Saurini F,Lechat P,Dandolo L,Hamon M,Mallet J,Vodjdani G

    更新日期:2003-11-11 00:00:00

  • Comparative mapping of Andropogoneae: Saccharum L. (sugarcane) and its relation to sorghum and maize.

    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

    authors: Guimarães CT,Sills GR,Sobral BW

    更新日期:1997-12-23 00:00:00

  • Further clues concerning the vectors essential to regulation of hexose transport, as studied in fibroblast cultures from a metabolic mutant.

    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

    authors: Kalckar HM,Ullrey DB

    更新日期:1984-02-01 00:00:00

  • Lack of p21 expression links cell cycle control and appendage regeneration in mice.

    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

    authors: Bedelbaeva K,Snyder A,Gourevitch D,Clark L,Zhang XM,Leferovich J,Cheverud JM,Lieberman P,Heber-Katz E

    更新日期:2010-03-30 00:00:00

  • Ab initio molecular dynamics and quasichemical study of H+(aq).

    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

    doi:10.1073/pnas.0408071102

    authors: Asthagiri D,Pratt LR,Kress JD

    更新日期:2005-05-10 00:00:00

  • Nicking-closing enzyme assembles nucleosome-like structures in vitro.

    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

    authors: Germond JE,Rouvière-Yaniv J,Yaniv M,Brutlag D

    更新日期:1979-08-01 00:00:00

  • The wing of the enhancer-binding domain of Mu phage transposase is flexible and is essential for efficient transposition.

    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

    authors: Clubb RT,Mizuuchi M,Huth JR,Omichinski JG,Savilahti H,Mizuuchi K,Clore GM,Gronenborn AM

    更新日期:1996-02-06 00:00:00

  • Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells.

    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

    authors: Jankovic V,Ciarrocchi A,Boccuni P,DeBlasio T,Benezra R,Nimer SD

    更新日期:2007-01-23 00:00:00

  • Evolution of global marine fishing fleets and the response of fished resources.

    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

    authors: Rousseau Y,Watson RA,Blanchard JL,Fulton EA

    更新日期:2019-06-18 00:00:00

  • MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells.

    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

    authors: Ploper D,Taelman VF,Robert L,Perez BS,Titz B,Chen HW,Graeber TG,von Euw E,Ribas A,De Robertis EM

    更新日期:2015-02-03 00:00:00

  • Omega-3 long-chain polyunsaturated fatty acids support aerial insectivore performance more than food quantity.

    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

    authors: Twining CW,Brenna JT,Lawrence P,Shipley JR,Tollefson TN,Winkler DW

    更新日期:2016-09-27 00:00:00

  • Five-S-isotope evidence of two distinct mass-independent sulfur isotope effects and implications for the modern and Archean atmospheres.

    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

    authors: Lin M,Zhang X,Li M,Xu Y,Zhang Z,Tao J,Su B,Liu L,Shen Y,Thiemens MH

    更新日期:2018-08-21 00:00:00

  • Directional selection is the primary cause of phenotypic diversification.

    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

    authors: Rieseberg LH,Widmer A,Arntz AM,Burke JM

    更新日期:2002-09-17 00:00:00

  • Inhibition of DNA synthesis in animal cells by ethylene diamine tetraacetate, and its reversal by zinc.

    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

    authors: Rubin H

    更新日期:1972-03-01 00:00:00

  • Intermolecular complementation between two defective mutant signal-transducing receptors of Escherichia coli.

    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

    authors: Yang Y,Inouye M

    更新日期:1991-12-15 00:00:00

  • Oligomeric intermediate in peptidoglycan biosynthesis in Bacillus megaterium.

    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

    authors: Fuchs-Cleveland E,Gilvarg C

    更新日期:1976-11-01 00:00:00