排序方式: 共有37条查询结果,搜索用时 31 毫秒
1.
Seo-Jung Han Jae Eun Jung Do Hee Oh Minsup Kim Jae-Min Kim Kyung-Sook Chung Hee-Soo Han Jeong-Hun Lee Kyung-Tae Lee Hee Jin Jeong In Ho Park Eunkyeong Jeon Jeon-Soo Shin Dongkeun Hwang Art E. Cho Duck-Hyung Lee Taebo Sim 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1257
Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region. 相似文献
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Chen P Norris D Das J Spergel SH Wityak J Leith L Zhao R Chen BC Pitt S Pang S Shen DR Zhang R De Fex HF Doweyko AM McIntyre KW Shuster DJ Behnia K Schieven GL Barrish JC 《Bioorganic & medicinal chemistry letters》2004,14(24):6061-6066
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. 相似文献
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Nakashima I Takeda K Kawamoto Y Okuno Y Kato M Suzuki H 《Archives of biochemistry and biophysics》2005,434(1):3-10
Protein tyrosine kinases (PTKs) play key roles in starting the signal transduction network for cellular development and functions. A number of both receptor-type and non-receptor-type PTKs, which are normally at a resting state, are initially activated in association with functions of the cell membrane and membrane rafts. Results of recent studies have suggested that these membrane-associated mechanisms for activation of PTKs consist of the two steps that are under redox control. The first step is activation of cell surface receptors through chemical crosslinkage or aggregation of receptors and membrane rafts, which leads to production of reactive oxygen species (ROS) as second messengers of intracellular signal transduction. The second step involves chemical modification of PTKs at the highly conserved cysteine in the MXXCW motif as a global switch for starting the tyrosine phosphorylation-dependent local switch for activation of the catalytic activity of the enzyme. 相似文献
5.
Kim MJ Park MT Yoon CH Byun JY Lee SJ 《Biochemical and biophysical research communications》2008,370(2):353-358
Despite extensive investigation, the molecular mechanism of anticancer activity of sphingolipid metabolites remains to be clarified. Here we demonstrate that sphingosine induces mitochondrial cell death via Lck-mediated conformational activation of Bak in Jurkat T cell lymphoma. Treatment of cells with sphingosine rapidly induced mitochondrial membrane potential loss, cytochrome c release from mitochondria, and apoptotic cell death. Sphingosine also induced conformational activation of Bak, but not Bax. siRNA targeting of Bak effectively attenuated sphingosine-induced mitochondrial cell death, indicating that Bak is involved in sphingosine-induced mitochondrial cell death. Sphingosine also induced activation of tyrosine kinase Lck. Inhibition of Lck by treatment of PP2, a Lck inhibitor or siRNA targeting of Lck suppressed sphingosine-induced conformational activation and oligomerization of Bak, mitochondrial membrane potential loss, and apoptotic cell death, implying that activation of Lck is critically required for sphingosine-induced conformational activation of Bak and mitochondrial cell death. The results elucidated in this study provide a novel cellular mechanism for the anticancer activity of sphingolipid metabolites. 相似文献
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Nonionic detergent lysates of cells contain a glycolipid-enriched membrane (GEM) fraction. It has been proposed that the GEM fraction represents poorly solubilized GEM microdomains, or lipid rafts. However, the properties of GEM domains in intact cells remain controversial. To study the properties of a GEM-associated protein using confocal microscopy, GFP was targeted to GEM domains using the N-terminal domain of p56(lck) (LckNT). Imaging of HeLa cells expressing LckNT-GFP showed that it was targeted to large actin-rich patches in the plasma membrane that contained up to a fivefold enrichment of protein. Double-labeling experiments showed that the patches were selectively enriched with other GEM-associated molecules. Furthermore, the patches were resistant to extraction by TX-100, and disrupting GEM domains by extracting cholesterol also disrupted colocalization of LckNT-GFP with F-actin. Analogous to the actin-rich patches in HeLa cells, LckNT-GFP colocalized with actin-rich membrane caps in stimulated T cells. Furthermore, disrupting the GEM-targeting signal of LckNT-GFP also inhibited its targeting to membrane caps. Altogether, these findings extend previous studies by showing that association of GEM domains with the actin cytoskeleton provides a mechanism for targeting signaling molecules to membrane patches and caps. 相似文献
7.
Determination of the solution structure of the SH3 domain of human p56 Lck tyrosine kinase 总被引:2,自引:0,他引:2
Summary The solution structure of the SH3 domain of human p56 Lck tyrosine kinase (Lck-SH3) has been determined by multidimensional heteronuclear NMR spectroscopy. The structure was calculated from a total of 935 experimental restraints comprising 785 distance restraints derived from 1017 assigned NOE cross peaks and 150 dihedral angle restraints derived from 160 vicinal coupling constants. A novel combination of the constant-time 1H–13C NMR correlation experiment recorded with various delays of the constant-time refocusing delays and a fractionally 13C-labelled sample was exploited for the stereo-specific assignment of prochiral methyl groups. Additionally, 28 restraints of 14 identified hydrogen bonds were included. A family of 25 conformers was selected to characterize the solution structure. The average root-mean-square deviations of the backbone atoms (N, C, C, O) among the 25 conformers is 0.42 Å for residues 7 to 63. The N- and C-terminal residues, 1 to 6 and 64 to 81, are disordered, while the well-converged residues 7 to 63 correspond to the conserved sequences of other SH3 domains. The topology of the SH3 structure comprises five anti-parallel -strands arranged to form two perpendicular -sheets, which are concave and twisted in the middle part. The overall secondary structure and the backbone conformation of the core -strands are almost identical to the X-ray structure of the fragment containing the SH2-SH3 domains of p56 Lck [Eck et al. (1994) Nature, 368, 764–769]. The X-ray structure of the SH3 domain in the tandem SH2-SH3 fragment is spatially included within the ensemble of the 25 NMR conformers, except for the segment of residues 14 to 18, which makes intermolecular contacts with an adjacent SH2 molecule and the phosphopeptide ligand in the crystal lattice. Local structural differences from other known SH3 domains are also observed, the most prominent of which is the absence in Lck-SH3 of the two additional short -strands in the regions Ser15 to Glu17 and Gly25 to Glu27 flanking the so-called RT-Src loop. This loop (residues Glu17 to Leu24), together with the n-Src loop (residues Gln37 to Ser46) confines the ligand interaction site which is formed by a shallow patch of hydrophobic amino acids (His14, Tyr16, Trp41, Phe54 and Phe59). Both loops are flexible and belong to the most mobile regions of the protein, which is assessed by the heteronuclear 15N,1H-NOE values characterizing the degree of internal backbone motions. The aromatic residues of the ligand binding site are arranged such that they form three pockets for interactions with the polyproline ligand.Abbreviations CT
constant time
- HSQC
heteronuclear single-quantum coherence
- NOE
nuclear Overhauser enhancement
- NOESY
nuclear Overhauser enhancement spectroscopy
- SH2
Src homology domain 2
- SH3
Src homology domain 3 相似文献
8.
Maud Kamal Andre Pawlak Fatima BenMohamed Asta Valanciuté Karine Dahan Marina Candelier Philippe Lang Georges Guellaën Djillali Sahali 《FEBS letters》2010,584(3):500-320
In naive T cells, Lck exerts a negative control on the ERK/MAPK pathway. We show that c-mip (c-maf inducing protein) interacts with the p85 subunit of PI3 kinase and inactivates Lck, which results in Erk1/2 and p38 MAPK activation. This effect is not enough to activate AP1 given the inability of ERK to migrate into the nucleus and to transactivate its target genes. We demonstrate that c-mip interacts with Dip1 and upregulates DAPK, which blocks the nuclear translocation of ERK1/2. This dual effect of c-mip is unique and might represent a potential mechanism to prevent the development of an immune response.
Structured summary
MINT-7383650: p85 (uniprotkb:P27986) physically interacts (MI:0915) with c-Mip (uniprotkb:Q8IY22) by anti bait coimmunoprecipitation (MI:0006)MINT-7383661: c-Mip (uniprotkb:Q8IY22) physically interacts (MI:0915) with p85 (uniprotkb:P27986) by anti tag coimmunoprecipitation (MI:0007)MINT-7383676: p85 (uniprotkb:P27986) physically interacts (MI:0915) with p110 (uniprotkb:P42336) by anti bait coimmunoprecipitation (MI:0006)MINT-7383689, MINT-7383711: Dip-1 (uniprotkb:Q80SY4) physically interacts (MI:0915) with c-Mip (uniprotkb:Q8IY22) by anti tag coimmunoprecipitation (MI:0007) 相似文献9.
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Within seconds of T cell receptor engagement, a well-characterized series of tyrosine phosphorylation events mediate cellular activation. It is widely accepted that these initial phosphorylations remain stable until protein tyrosine phosphatases return the cell to its basal level. Based on a model of peripheral blood T cell activation, in which the kinetics of phosphorylation can be modulated, we propose an alternate hypothesis that T cell signaling is highly dynamic. Our results demonstrate that tyrosine phosphorylation and dephosphorylation are occurring co-temporally after T cell receptor cross-linking, regulated by a delicate balance of kinases and phosphatases. 相似文献