Increasing the Kinase Specificity of K252a by Protein Surface Recognition

Schneider, Tanya L.; Mathew, Rebecca; Rice, Kevin P.; Tamaki, Koreaki; Wood, John L.; Schepartz, Alanna

doi:10.1021/ol050179o

Cited by 52 publications

(40 citation statements)

References 47 publications

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“…6C). To corroborate results obtained with TrkB-Fc, effects of the tyrosine and serine/threonine kinase inhibitor K252a (Schneider et al, 2005), which blocks signaling through the Trk neurotrophin receptors but not through p75 (Knusel and Hefti, 1992;Scharfman, 1997;Cosgaya et al, 2002;Cheng and Yeh, 2005;Skoff and Adler, 2006), were examined. K252a applied at 2 M does not alter basal synaptic transmission (Rex and Lynch, unpublished observations) and in the present studies did not affect the number of densely labeled spine profiles under baseline stimulation conditions (9 Ϯ 3 vs 11 Ϯ 4 for control vs control ϩ K252a, respectively; p Ͼ 0.4, two-tailed t test; n ϭ 3 per group).…”

Section: Bdnf Promotes Theta Stimulationinduced Actin Polymerizationmentioning

confidence: 91%

Brain-Derived Neurotrophic Factor Promotes Long-Term Potentiation-Related Cytoskeletal Changes in Adult Hippocampus

Rex¹,

Lin²,

Kramár³

et al. 2007

J. Neurosci.

292

236

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Brain-derived neurotrophic factor (BDNF) is an extremely potent, positive modulator of theta burst induced long-term potentiation (LTP) in the adult hippocampus. The present studies tested whether the neurotrophin exerts its effects by facilitating cytoskeletal changes in dendritic spines. BDNF caused no changes in phalloidin labeling of filamentous actin (F-actin) when applied alone to rat hippocampal slices but markedly enhanced the number of densely labeled spines produced by a threshold level of theta burst stimulation. Conversely, the BDNF scavenger TrkB-Fc completely blocked increases in spine F-actin produced by suprathreshold levels of theta stimulation. TrkB-Fc also blocked LTP consolidation when applied 1-2 min, but not 10 min, after theta trains. Additional experiments confirmed that p21 activated kinase and cofilin, two actin-regulatory proteins implicated in spine morphogenesis, are concentrated in spines in mature hippocampus and further showed that both undergo rapid, dose-dependent phosphorylation after infusion of BDNF. These results demonstrate that the influence of BDNF on the actin cytoskeleton is retained into adulthood in which it serves to positively modulate the time-dependent LTP consolidation process.

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Section: Bdnf Promotes Theta Stimulationinduced Actin Polymerizationmentioning

confidence: 91%

Brain-Derived Neurotrophic Factor Promotes Long-Term Potentiation-Related Cytoskeletal Changes in Adult Hippocampus

Rex¹,

Lin²,

Kramár³

et al. 2007

J. Neurosci.

292

236

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“…[52] Finally, a bisubstrate inhibitor with remarkable selectivity towards PKAc was obtained by connecting staurosporine analogue K252a with a miniature protein containing a fragment of PKI sequence (compound 14). [53] The conjugate exhibited an IC 50 value of 3.6 nm against PKAc, while an IC 50 value of 680 nm was obtained against PKG1 and even lower affinity for the other tested PKs (PKB, PKCa, CAMK-II). Unfortunately, the cost of K252a and high molecular mass of its peptide conjugate (> 5500 kDa) limit the large-scale production of compound 14.…”

Section: Conjugates Of Peptides With Potent Atp-competitive Inhibitorsmentioning

confidence: 94%

Bisubstrate Inhibitors of Protein Kinases: from Principle to Practical Applications

2009

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Bisubstrate inhibitors consist of two conjugated fragments, each targeted to a different binding site of a bisubstrate enzyme. The design of bisubstrate inhibitors presupposes the formation of the ternary complex in the course of the catalyzed reaction. The principle advantage of bisubstrate inhibitors is their ability to generate more interactions with the target enzyme that could result in improved affinity and selectivity of the conjugates, when compared with single-site inhibitors. Among phosphotransferases, the approach was first successfully used for adenylate kinase in 1973. Since then, several types of bisubstrate inhibitors have been developed for protein kinases, including conjugates of peptides with nucleotides, adenosine derivatives and potent ATP-competitive inhibitors. Earlier bisubstrate inhibitors had pharmacokinetic qualities that were unsuitable for cellular experiments and hence were mostly used for in vitro studies. The recently constructed conjugates of adenosine derivatives and D-arginine-rich peptides (ARCs) possess high kinase affinity, high biological and chemical stability and good cell plasma membrane penetrative properties that enable their application in the regulation of cellular protein phosphorylation balances in cell and tissue experiments.

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“…Subsequent second-and third-generation library synthesis resulted in a small grafted protein displaying a K i value of 35 nM for hDM2 binding. Further studies included investigations into miniature proteins designed to mimic the kinase-inducible activation domain (KID) of the transcription factor CREB with the KIX domain of the transcriptional coactivator protein CPB, [15] as well as that of the cAMP-dependent protein kinase recognition epitope found in the heat-stable protein kinase inhibitor protein [16].…”

Section: Miniature Protein Motifsmentioning

confidence: 99%

Scaffolds for Blocking Protein-Protein Interactions

Hershberger¹,

Lee²,

Chmielewski

2007

CTMC

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Due to the pivotal roles that protein-protein interactions play in a plethora of biological processes, the design of therapeutic agents targeting these interactions has become an attractive and important area of research. The development of such agents is faced with a variety of challenges. Nevertheless, considerable progress has been made in the design of proteomimetics capable of disrupting protein-protein interactions. Those inhibitors based on molecular scaffold designs hold considerable interest because of the ease of variation in regard to their displayed functionality. In particular, protein surface mimetics, alpha-helical mimetics, beta-sheet/beta-strand mimetics, as well as beta-turn mimetics have successfully modulated protein-protein interactions involved in such diseases as cancer and HIV. In this review, current progress in the development of molecular scaffolds designed for the disruption of protein-protein interactions will be discussed with an emphasis on those active against biological targets.

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Increasing the Kinase Specificity of K252a by Protein Surface Recognition

Cited by 52 publications

References 47 publications

Brain-Derived Neurotrophic Factor Promotes Long-Term Potentiation-Related Cytoskeletal Changes in Adult Hippocampus

Brain-Derived Neurotrophic Factor Promotes Long-Term Potentiation-Related Cytoskeletal Changes in Adult Hippocampus

Bisubstrate Inhibitors of Protein Kinases: from Principle to Practical Applications

Scaffolds for Blocking Protein-Protein Interactions

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