Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

K(+) channels are universally involved in electrical activity in muscles and nerves, and also in regulating salt and water transport in tissues implicated in metabolism. The prokaryotic KcsA K(+) channel has become a structural archetype for the pore domain of voltage-dependent channels. The binding of the inactivating peptide from the eukaryotic Shaker B K(+) channel (ShB peptide) to either asolectin-reconstituted or DDM-solubilised KcsA has been shown to occur mainly through the hydrophobic region of the peptide (namely, residues Val4, Tyr8, Leu7 and Leu10). In this work, we studied the binding of a deletion variant of the ShB peptide, where the first 11 residues, and then, the hydrophobic region, have been removed (Delta(1-11)ShB). The aim of this work is to elucidate whether binding to KcsA can also occur through the highly charged C-terminal region of ShB peptide. The STD-NMR experiments indicate that there is binding of Delta(1-11)ShB to either asolectin-reconstituted or DDM-solubilised KcsA. The protons showing the largest effects are those of the side-chain of His16, and probably, the backbone amide protons of both Lys18 and Lys19. These results indicate that the hydrophobic residues in ShB peptide are not necessary to ensure binding to the channel, and then, binding to KcsA is also driven by electrostatic interactions.
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PMID:The positively charged C-terminal region of the inactivating Shaker B peptide binds to the potassium channel KcsA. 1932 3

Hexokinase catalyzes the phosphorylation of glucose and is the first enzyme in glycolysis. To investigate enzyme-ligand interactions in yeast hexokinase isoform PII under physiological conditions, we utilized the technique of Saturation Transfer Difference NMR (STD NMR) to monitor binding modes and binding affinities of different ligands at atomic resolution. These experiments clearly show that hexokinase tolerates several changes at C-2 of its main substrate glucose, whereas epimerization of C-4 significantly reduces ligand binding. Although both glucose anomers bind to yeast hexokinase, the alpha-form is the preferred form for the phosphorylation reaction. These findings allow mapping of tolerated and prohibited modification sites on the ligand. Furthermore, competitive titration experiments show that mannose has the highest binding affinity of all examined sugars. As several naturally occurring sugars in cells show binding affinities in a similar range, hexokinase may be considered as an 'emergency enzyme' in yeast cells. Taken together, our results represent a comprehensive analysis of ligand-enzyme interactions in hexokinase PII and provide a valuable basis for inhibitor design and metabolic engineering.
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PMID:Specificity of ligand binding to yeast hexokinase PII studied by STD-NMR. 1936 94

A novel chemically sulfated polysaccharide SRBPS2a with potent anti-tumor activity was derived from defatted rice bran by chlorosulfonic acid-pyridine (CSA-Pyr) method. The average molecular weight of SRBPS2a was 3.5 x 10(5) Da and the degree of sulfation (DS) was 1.29. The Fourier-transform infrared spectra (FT-IR) and 13C NMR spectroscopy analysis revealed that SRBPS2a was mainly consist of beta-(1-->3)-D-galactopyranosyl residues, the sulfate substitution site was on C-2 and C-4 while the side chains were cut off during the sulfated reaction. Furthermore, SRBPS2a exhibited evident growth inhibition on mouse mammary tumor EMT-6 cells both in vitro and in vivo.
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PMID:Characterization and anti-tumor activities of sulfated polysaccharide SRBPS2a obtained from defatted rice bran. 1954 38

A procedure was developed for the quantitative determination of chafuroside A, a flavone C-glycoside with potent anti-inflammatory activity, and its regioisomer chafuroside B, as well as isovitexin and vitexin, by selected reaction monitoring liquid chromatography-tandem mass spectrometry (SRM LC-MS/MS) analysis. This method was successfully applied to commercial leaves of green tea, houji tea, oolong tea, and black tea. High levels of chafurosides A and B were found in oolong tea leaves that had been heated at >140 degrees C. Next, their precursors, prechafurosides A and B, were isolated from methanol extract of oolong tea leaves prepared from Shizu 7132, Camellia sinensis (L.) O. Kuntze, by partition with n-butanol and H2O and chromatography on Diaion SP-825, Sephadex LH-20, and ODS C-18, guided by assay of chafuroside formation. Prechafurosides A and B gave chafurosides A and B, respectively, in good yields when heated at 160 degrees C for 0.5 h. Solvolysis of prechafurosides A and B with pyridine and dioxane quantitatively afforded isovitexin and vitexin, respectively. On the basis of these results and physicochemical data (MS, UV, and NMR), prechafurosides A and B were concluded to be new flavone C-glycoside sulfates, isovitexin-2''-sulfate and vitexin-2''-sulfate, respectively.
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PMID:Quantitation of chafurosides A and B in tea leaves and isolation of prechafurosides A and B from oolong tea leaves. 1957 51

The solution and solid state conformations of several 6-O-methyl homoerythromycins 1-4 were studied using a combination of X-ray crystallography, NMR spectroscopy and molecular modelling calculations. In the solid state 1 was found to exist as the two independent molecules with similar structures termed 3-endo-folded-out. In solution a significant conformational flexibility was noticed especially in the C2 to C5 region. The compounds 1 and 2 unlike 14-membered macrolides adopted the 3-endo-folded-out conformation while 3 and 4 existed in the classical folded-out conformation. TrNOESY and STD experiments showed that 1 and 2 bound to the Escherichia coli ribosome while 3 and 4, lacking the cladinose sugar, did not exhibit binding activities, this being in accordance with biochemical data. The bound conformations were found to be very similar to the free ones, some small differences were observed and discussed. The STD experiments provided evidence on binding epitopes. The structural parts of 1 and 2 in close contact with ribosome were similar, however the degree of saturation transfer was higher for 2. The differences between tr-NOE data and STD enhancements in 1 and 2 arouse as a consequence of structural changes upon binding and a closer proximity of 2 to the ribosome surface. An understanding of the molecular mechanisms involved in the interaction of macrolides with ribosomes can help in developing strategies aiming at design of potential inhibitors.
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PMID:Free and bound state structures of 6-O-methyl homoerythromycins and epitope mapping of their interactions with ribosomes. 1962 98

Imatinib (Glivec or Gleevec) potently inhibits the tyrosine kinase activity of BCR-ABL, a constitutively activated kinase, which causes chronic myelogenous leukemia (CML). Here we report the first almost complete backbone assignment of c-ABL kinase domain in complex with imatinib.
Biomol NMR Assign 2008 Jun
PMID:Backbone NMR resonance assignment of the Abelson kinase domain in complex with imatinib. 1963 20

FtsZ is a prokaryotic tubulin-like protein. Despite a low degree of sequence identity with tubulin, it presents the same folding pattern and some similar functions, notably in cell division. Indeed, FtsZ and tubulin polymerize to form bundles and microtubules, respectively, which are essential for cell cytokinesis. We previously demonstrated that peptides derived from the N-terminal stathmin domain interact with tubulin and impede microtubule formation. We demonstrated here that I19L, the most efficient of these peptides, also alters FtsZ bundling assembly in vitro. STD-NMR and TRNOESY experiments revealed that I19L interacts with FtsZ and folds upon its binding but in a way different from what we observed with tubulin. These NMR data were used in molecular modeling calculations to propose models of the I19L-FtsZ complex. Interestingly, two models, consistent with NMR data, show an interaction of I19L near the T7 loop or near the GTP binding site of FtsZ, explaining the modifications of the bundling assembly observed with this peptide. The fine analysis of the structural differences of the complexes of I19L with FtsZ and tubulin should help for the rational development of new specific antibiotic agents.
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PMID:The stathmin-derived I19L peptide interacts with FtsZ and alters its bundling. 1974 36

The binding kinetics of disaccharides trehalose and trehalose-6-phosphate to repressor protein TreR have been determined using STD NMR and shed light on the contrasting biological roles of these two sugars.
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PMID:Saturation transfer difference NMR reveals functionally essential kinetic differences for a sugar-binding repressor protein. 1978 22

BTK-2, a 32 residue scorpion toxin initially identified in the venom of red Indian scorpion Mesobuthus tamulus was cloned, overexpressed and purified using Cytochrome b(5) fusion protein system developed in our laboratory. The synthetic gene coding for the peptide was designed taking into account optimal codon usage by Escherichia coli. High expression levels of the fusion protein enabled facile purification of this peptide. The presence of disulfide bonded isomers, occurring as distinctly populated states even in the fusion protein, were separated by gel filtration chromatography. The target peptide was liberated from the host protein by Tev protease cleavage and subsequent purification was achieved using RP-HPLC methods. Reverse phase HPLC clearly showed the presence of at least two isomeric forms of the peptide that were significantly populated. The oxidative folding of BTK-2 was achieved under ambient conditions during the course of purification. Structural characterization of the two forms, by solution homonuclear and heteronuclear NMR methods, has shown that these two forms exhibit significantly different structural properties, and represent the natively folded and a "misfolded" form of the peptide. The formation of properly folded BTK-2 as a major fraction without the use of in vitro oxidative refolding methods clearly indicate the versatility of the Cytochrome b(5) fusion protein system for the efficient production of peptides for high resolution NMR studies.
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PMID:Cloning, overexpression, folding and purification of a biosynthetically derived three disulfide scorpion toxin (BTK-2) from Mesobuthus tamulus. 1988 10

Galectin-1 (Gal-1), a ubiquitous beta-galactoside-binding protein expressed by various normal and pathological tissues, has been implicated in cancer and autoimmune/inflammatory diseases in consequence of its regulatory role in adhesion, cell viability, proliferation, and angiogenesis. The functions of Gal-1 depend on its affinity for beta-galactoside-containing glycoconjugates; accordingly, the inhibition of sugar binding blocks its functions, hence promising potential therapeutic tools. The Tyr-Xxx-Tyr peptide motifs have been reported to be glycomimetic sequences, mainly on the basis of their inhibitory effect on the Gal-1-asialofetuin (ASF) interaction. However, the results regarding the efficacy of the Tyr-Xxx-Tyr motif as a glycomimetic inhibitor are still controversial. The present STD and trNOE NMR experiments reveal that the Tyr-Xxx-Tyr peptides studied do not bind to Gal-1, whereas their binding to ASF is clearly detected. (15)N,(1)H HSQC titrations with (15)N-labeled Gal-1 confirm the absence of any peptide-Gal-1 interaction. These data indicate that the Tyr-Xxx-Tyr peptides tested in this work are not glycomimetics as they interact with ASF via an unrevealed molecular linkage.
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PMID:Galectin-1-asialofetuin interaction is inhibited by peptides containing the tyr-xxx-tyr motif acting on the glycoprotein. 1993 27


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