Abstract:
:The ras oncogene products (H-Ras, K-Ras, and N-Ras) have been regarded as some of the most promising targets for anticancer drug discovery because their activating mutations are frequently found in human cancers. Nonetheless, molecular targeted therapy for them is currently unavailable. Here, we report the discovery of a small-molecule compound carrying a naphthalene ring, named KBFM123, which binds to the GTP-bound form of H-Ras. The solution structure of its complex with the guanosine 5'-(β,γ-imide) triphosphate-bound form of H-RasT35S (H-RasT35S·GppNHp) indicates that the naphthalene ring of KBFM123 interacts directly with a hydrophobic pocket located between switch I and switch II and allosterically inhibits the effector interaction by inducing conformational changes in switch I and its flanking region in strand β2, which are directly involved in recognition of the effector molecules, including c-Raf-1. In particular, Asp38 of H-Ras, a crucial residue for the interaction with c-Raf-1 via the formation of a salt bridge with Arg89 of the Ras-binding domain (RBD) of c-Raf-1, shows a drastic conformational change: its side chain orients toward the opposite direction. Consistent with these results, KBFM123 exhibits an activity to inhibit, albeit weakly, the association of H-RasG12V·GppNHp with the c-Raf-1 RBD. The binding of the naphthalene ring to the hydrophobic pocket of H-RasT35S·GppNHp is further supported by nuclear magnetic resonance analyses showing that two other naphthalene-containing compounds with distinct structures also exhibit similar binding properties with KBFM123. These results indicate that the naphthalene ring could become a promising scaffold for the development of Ras inhibitors.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Matsumoto S,Hiraga T,Hayashi Y,Yoshikawa Y,Tsuda C,Araki M,Neya M,Shima F,Kataoka Tdoi
10.1021/acs.biochem.8b00680subject
Has Abstractpub_date
2018-09-11 00:00:00pages
5350-5358issue
36eissn
0006-2960issn
1520-4995journal_volume
57pub_type
杂志文章相关文献
BIOCHEMISTRY文献大全abstract::High-molecular mass thioredoxin reductases (TRs) are pyridine nucleotide disulfide oxidoreductases that catalyze the reduction of the disulfide bond of thioredoxin (Trx). Trx is responsible for reducing multiple protein disulfide targets in the cell. TRs utilize reduced β-nicotinamide adenine dinucleotide phosphate to...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi400931k
更新日期:2014-01-28 00:00:00
abstract::To test whether the Y-shaped conformation of the hammerhead ribozyme is maintained throughout the catalytic pathway, the cleavage properties of circular substrates which bind the ribozyme through helices I and II were determined. Constraining the position of helices I and II in this manner did not significantly alter ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi980307z
更新日期:1998-06-30 00:00:00
abstract::The active site of water oxidation in Photosystem II (PSII) is a Mn4CaO5 cluster that is located in a cavity between the D1 and CP43 protein subunits by which it is coordinated. The remainder of this cavity is filled with water molecules, which serve as a source of substrate and participate in poorly understood hydrog...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi400930g
更新日期:2013-10-01 00:00:00
abstract::The dynamic equilibrium of a catalytic site between active and inactive conformations, the missing link between the structure and function of allosteric enzymes, was identified using protein engineering and NMR techniques. Kinetic analyses of the wild-type and three mutants of Thermus L-lactate dehydrogenase establish...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00138a017
更新日期:1992-06-16 00:00:00
abstract::Two hybrid ribulose-1,5 bisphosphate carboxylase/oxygenase (RubisCO) enzymes were constructed using RubisCO small subunit genes (rbcS) from two eucaryotic marine organisms, Cylindrotheca sp. N1 and Olisthodiscus luteus, cloned downstream of the RubisCO large subunit gene (rbcL) of the cyanobacterium Synechococcus PCC ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00139a018
更新日期:1992-06-23 00:00:00
abstract::Voltage-dependent anion channel 1 (VDAC1) situated in the outer mitochondrial membrane regulates the transfer of various metabolites and is a key player in mitochondria-mediated apoptosis. Although many small chemicals that modulate the functions of VDAC1 have been reported to date, most, if not all, of them cannot be...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/acs.biochem.8b01209
更新日期:2019-02-26 00:00:00
abstract::In aqueous glycerol solutions, the rate constant for the formation of compound I of horseradish peroxidase from hydrogen peroxide is independent of the viscosity. However, whem m-chloroperbenzoic acid is used to form compound I, the rate is viscosity dependent, indicating that this reaction is diffusion controlled. Th...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00632a023
更新日期:1977-06-28 00:00:00
abstract::The interactions of Hoechst 33377 (H1) with 20 different oligomeric duplexes have been investigated via spectrofluorometric titrations and/or thermal denaturation experiments. H1 is shown to form 2:1 complexes with dsDNA binding sites of at least four contiguous A/T base pairs. H1 is also shown to possess the rare abi...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi0103415
更新日期:2001-05-29 00:00:00
abstract::Studies are presented of the equilibrium binding of [3H]-d-tubocurarine (dTC) and [3H]acetylcholine (AcCh) to Torpedo postsynaptic membranes. The saturable binding of [3H]dTC is characterized by two affinities: Kd1 = 33 +/- 6 nM and Kd2 = 7.7 +/- 4.6 microM, with equal numbers of binding sites. Both components are com...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00591a032
更新日期:1979-11-27 00:00:00
abstract::The recA locus of pathogenic mycobacteria differs from that of nonpathogenic species because it contains large intervening sequences nested in the RecA homology region that are excised by an unusual protein-splicing reaction. In vivo assays indicated that Mycobacterium tuberculosis recA partially complemented Escheric...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi9517751
更新日期:1996-02-13 00:00:00
abstract::Guided by the X-ray structure analysis of a crystalline EcoRV-d(GGGATATCCC) complex (Winkler, in preparation), we have begun to identify functionally important amino acid residues of EcoRV. We show here that Asn70, Asp74, Ser183, Asn185, Thr186, and Asn188 are most likely involved in the binding and/or cleavage of the...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00240a011
更新日期:1991-07-02 00:00:00
abstract::MT1-MMP, a prototypic member of a membrane-type metalloproteinase subfamily, is an invasion promoting protease and an activator of MMP-2. In addition, MT1-MMP proteolysis regulates the functionality of cell-surface adhesion/signaling receptors including tissue transglutaminase (tTG). tTG is known to serve as an adhesi...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi049266z
更新日期:2004-09-21 00:00:00
abstract::The effects of phosphorylation at Ser40 of rat tyrosine hydroxylase on the affinities of catechols have been determined with both the ferric and ferrous forms of the enzyme. Phosphorylation had no effect on the Ki value for the inhibition of the ferrous enzyme by either dopamine or DOPA when the initial rate of turnov...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi980582l
更新日期:1998-06-23 00:00:00
abstract::The backbone dynamics of uniformly 15N-labeled interleukin-1 beta are investigated by using two-dimensional inverse detected heteronuclear 15N-1H NMR spectroscopy. 15N T1, T2, and NOE data at a spectrometer frequency of 600 MHz are obtained for 90% of the backbone amide groups. The data provide evidence for motions on...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00484a006
更新日期:1990-08-14 00:00:00
abstract::Phosphoenolthiopyruvate, the analogue of phosphoenolpyruvate in which the bridging oxygen of the phosphate ester is replaced by sulfur, has been synthesized from methyl acrylate and dimethyl (chlorothio)phosphonate. The compound is a substrate for alkaline phosphatase, pyruvate kinase, enolase, and phosphoenolpyruvate...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00404a038
更新日期:1988-02-23 00:00:00
abstract::Segregation of mRNAs in the cytoplasm of polar cells has been demonstrated for proteins involved in Xenopus and Drosophila oogenesis, and for some proteins in somatic cells. It is assumed that vectorial transport of the messages is generally responsible for this localization. The mRNA encoding the basic protein of cen...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi9800247
更新日期:1998-05-12 00:00:00
abstract::Previous work has described the novel ability to modulate in vitro the activity of restriction endonuclease NaeI from Nocardia aerocoligenes by using cleavable DNA and spermidine [Conrad & Topal (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 9707-9711]. In this paper we report the results of a study of 49 type II restrictio...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00223a035
更新日期:1991-03-05 00:00:00
abstract::Oxindolealanine-62 lysozyme, formed by reaction with N-bromosuccinimide and purified by using affinity chromatography, was examined in its binding of homologous oligosaccharides of N-acetylglucosamine and in its catalysis of hydrolysis and of transglycosylation of the hexasaccharide of N-acetylglucosamine. Equilibrium...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00558a022
更新日期:1980-08-19 00:00:00
abstract::A new specific voltage-sensitive calcium channel (VSCC) blocker has been isolated from the venom of the fish-hunting cone snail Conus consors. This peptide, named omega-Ctx CNVIIA, consists of 27 amino acid residues folded by 3 disulfide bridges. Interestingly, loop 4, which is supposed to be crucial for selectivity, ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi002871r
更新日期:2001-12-04 00:00:00
abstract::Propeptide processing occurs in specific compartments of the secretory pathway, but how these processing-competent organelles are generated from their processing-incompetent precursor compartments is unknown. To dissect the process biochemically, we have developed a novel cell-free system reconstituting the production...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi0112762
更新日期:2001-10-30 00:00:00
abstract::Escherichia coli (A)BC excinuclease is the major enzyme responsible for removing bulky adducts, such as pyrimidine dimers and 6-4 photoproducts, from DNA. Mutants deficient in this enzyme are extremely sensitive to UV and UV-mimetic agents, but not to oxidizing agents, or ionizing radiation which damages DNA in part b...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00446a002
更新日期:1989-10-03 00:00:00
abstract::The primary ligand-binding protein (CNTFR alpha) of the multicomponent receptor for ciliary neurotrophic factor was produced in Escherichia coli. Using novel applications of size-exclusion chromatography and a protein gel-shift assay, we obtained quantitative separation of correctly refolded protein, as well as analyt...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00185a020
更新日期:1994-05-17 00:00:00
abstract::1,3-15N-Labeled uracil was synthesized chemically and used to prepare labeled Escherichia coli tRNA(Val) biosynthetically. 500-MHz measurements of 15N and proton chemical shift were obtained, for all uridine and uridine-related bases, by heteronuclear multiple-quantum coherence spectroscopy. All the uracil NH group re...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00166a013
更新日期:1992-12-29 00:00:00
abstract::Fourier transform infrared difference spectroscopy has been used to obtain information about substrate-induced structural changes of the melibiose permease (MelB) from Escherichia coli reconstituted into liposomes. Binding of the cosubstrate Na(+) gives rise to several peaks in the amide I and II regions of the differ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi048301z
更新日期:2005-03-08 00:00:00
abstract::ADP-glucose pyrophosphorylase (ADPGlc PPase) catalyzes the conversion of glucose 1-phosphate and ATP to ADP-glucose and pyrophosphate. As a key step in glucan synthesis, the ADPGlc PPases are highly regulated by allosteric activators and inhibitors in accord with the carbon metabolism pathways of the organism. Crystal...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi701933q
更新日期:2008-04-15 00:00:00
abstract::The temporal evolution of the near-infrared stimulated emission band of the special pair excited state (P*) in the reaction center of Rhodobacter sphaeroides has been studied in intracytoplasmic membranes of the antenna-deficient RCO1 mutant at 10 K with a resolution of 30 fs. On the 100-fs time scale the emission ban...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00188a002
更新日期:1994-06-07 00:00:00
abstract::Oxygenic photosynthesis in plants involves highly reactive intermediates and byproducts that can damage the photosynthetic apparatus and other chloroplast constituents. The potential for damage is exacerbated when the amount of absorbed light exceeds the capacity for light energy utilization in photosynthesis, a condi...
journal_title:Biochemistry
pub_type: 杂志文章,评审
doi:10.1021/bi0494020
更新日期:2004-07-06 00:00:00
abstract::A combination of mutagenesis, calorimetry, kinetics, and small-angle X-ray scattering (SAXS) has been used to study the mechanism of ligand binding energy propagation through human cytochrome P450 reductase (CPR). Remarkably, the energetics of 2',5'-ADP binding to R597 at the FAD-binding domain are affected by mutatio...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi700596s
更新日期:2007-07-17 00:00:00
abstract::The expression of the transforming gene product of Rous sarcoma virus (pp60v-src) in Saccharomyces cerevisiae has recently been reported (Kornbluth et al., 1987; Brugge et al., 1987). To carry out biochemical and structural studies of this enzyme, a facile purification was developed. The purification was accomplished ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00449a013
更新日期:1989-11-14 00:00:00
abstract::Proton nuclear magnetic resonance spectra of human hemoglobins in water reveal several exchangeable protons which are indicators of the quaternary structures of both the liganded and unliganded molecules. A comparison of the spectra of normal human adult hemoglobin with those of mutant hemoglobins Chesapeake (FG4alpha...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00682a036
更新日期:1975-06-03 00:00:00