当前位置： SCI文献检索 > BIOCHEMISTRY期刊下所有文献 > Inhibition and binding kinetics of the hepatitis C virus NS3 protease inhibitor ITMN-191 reveals tight binding and slow dissociative behavior.

Inhibition and binding kinetics of the hepatitis C virus NS3 protease inhibitor ITMN-191 reveals tight binding and slow dissociative behavior.

Abstract：

:The protease activity of hepatitis C virus nonstructural protein 3 (NS3) is essential for viral replication. ITMN-191, a macrocyclic inhibitor of the NS3 protease active site, promotes rapid, multilog viral load reductions in chronic HCV patients. Here, ITMN-191 is shown to be a potent inhibitor of NS3 with a two-step binding mechanism. Progress curves are consistent with the formation of an initial collision complex (EI) that isomerizes to a highly stable complex (EI*) from which ITMN-191 dissociates very slowly. K(i), the dissociation constant of EI, is 100 nM, and the rate constant for conversion of EI to EI* is 6.2 x 10(-2) s(-1). Binding experiments using protein fluorescence confirm this isomerization rate. From progress curve analysis, the rate constant for dissociation of ITMN-191 from the EI* complex is 3.8 x 10(-5) s(-1) with a calculated complex half-life of approximately 5 h and a true biochemical potency (K(i)*) of approximately 62 pM. Surface plasmon resonance studies and assessment of enzyme reactivation following dilution of the EI* complex confirm slow dissociation and suggest that the half-life may be considerably longer. Abrogation of the tight binding and slow dissociative properties of ITMN-191 is observed with proteases that carry the R155K or D168A substitution, each of which is likely in drug resistant mutants. Slow dissociation is not observed with closely related macrocyclic inhibitors of NS3, suggesting that members of this class may display distinct binding kinetics.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Rajagopalan R,Misialek S,Stevens SK,Myszka DG,Brandhuber BJ,Ballard JA,Andrews SW,Seiwert SD,Kossen K

doi

10.1021/bi900038p

subject

Has Abstract

pub_date

2009-03-24 00:00:00

pages

2559-68

issue

11

eissn

0006-2960

issn

1520-4995

pii

10.1021/bi900038p

journal_volume

48

pub_type

杂志文章

相关文献

BIOCHEMISTRY文献大全
  • Escherichia coli cAMP receptor protein-DNA complexes. 1. Energetic contributions of half-sites and flanking sequences in DNA recognition.

    abstract：:In Escherichia coli, the cyclic AMP receptor protein (CRP) serves as a sensor of the intracellular level of cyclic AMP. At increasing concentrations of cyclic AMP, CRP becomes activated upon binding a cyclic AMP molecule. The activated CRP is capable of regulating the expression of more than 20 genes by binding to spe...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi972450i

    authors： Pyles EA,Chin AJ,Lee JC

    更新日期：1998-04-14 00:00:00

  • An atomic-level mechanism for molybdenum nitrogenase. Part 1. Reduction of dinitrogen.

    abstract：:The properties of the Fe and Mo sites of the iron-molybdenum cofactor of nitrogenase with respect to binding and activation of N(2) have been studied by molecular mechanics calculations on the local protein environment and by density functional theory (DFT) calculations on subsections of the cofactor. The DFT calculat...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi025623z

    authors： Durrant MC

    更新日期：2002-11-26 00:00:00

  • Structure of the Rhodobacter sphaeroides light-harvesting 1 beta subunit in detergent micelles.

    abstract：:The light harvesting 1 antenna (LH1) complex from Rhodobacter sphaeroides funnels excitation energy to the photosynthetic reaction center. Our ultimate goal is to build up the structure of LH1 from structures of its individual subunits, much as the antenna can self-assemble from its components in membrane-mimicking de...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi011576j

    authors： Sorgen PL,Cahill SM,Krueger-Koplin RD,Krueger-Koplin ST,Schenck CC,Girvin ME

    更新日期：2002-01-08 00:00:00

  • A conserved threonine within Escherichia coli leucyl-tRNA synthetase prevents hydrolytic editing of leucyl-tRNALeu.

    abstract：:Aminoacyl-tRNA synthetases ensure the fidelity of protein synthesis by accurately selecting and activating cognate amino acids for aminoacylation of the correct tRNA. Some tRNA synthetases have evolved an editing active site that is separate from the amino acid activation site providing two steps or "sieves" for amino...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi002915w

    authors： Mursinna RS,Lincecum TL Jr,Martinis SA

    更新日期：2001-05-08 00:00:00

  • Crystal structure of homoserine transacetylase from Haemophilus influenzae reveals a new family of alpha/beta-hydrolases.

    abstract：:Homoserine transacetylase catalyzes one of the required steps in the biosynthesis of methionine in fungi and several bacteria. We have determined the crystal structure of homoserine transacetylase from Haemophilus influenzae to a resolution of 1.65 A. The structure identifies this enzyme to be a member of the alpha/be...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi051951y

    authors： Mirza IA,Nazi I,Korczynska M,Wright GD,Berghuis AM

    更新日期：2005-12-06 00:00:00

  • Targeted cross-linking of a molten globule form of acetylcholinesterase by the virucidal agent hypericin.

    abstract：:The natural product hypericin is a photosensitive polycyclic aromatic dione compound, which has been widely investigated because of its virucidal and antitumor properties. Although it has been suggested that singlet oxygen or a radical species might be responsible for its biological action, its mechanism of action rem...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi991147+

    authors： Weiner L,Roth E,Mazur Y,Silman I

    更新日期：1999-08-31 00:00:00

  • Solution structure of the first intracellular loop of prostacyclin receptor and implication of its interaction with the C-terminal segment of G alpha s protein.

    abstract：:The amino acids (residues 39-51) responsible for the interaction between the first intracellular loop (iLP1) of the human prostacyclin receptor (IP) and G alpha s protein have been identified [Zhang, L., Huang, G., Wu, J., and Ruan, K. H. (2005) Biochemistry 44, 11389-11401]. To further characterize the structural/fun...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi0515669

    authors： Zhang L,Wu J,Ruan KH

    更新日期：2006-02-14 00:00:00

  • Metal binding to Saccharomyces cerevisiae ferrochelatase.

    abstract：:Ferrochelatase is the terminal enzyme in the heme biosynthetic pathway. It catalyzes the insertion of ferrous iron into protoporphyrin IX to produce protoheme IX. The crystal structures of ferrochelatase from Saccharomyces cerevisiae in free form, in complex with Co(II), a substrate metal ion, and in complex with two ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi0260785

    authors： Karlberg T,Lecerof D,Gora M,Silvegren G,Labbe-Bois R,Hansson M,Al-Karadaghi S

    更新日期：2002-11-19 00:00:00

  • On the identity of nuclear membrane and non-histone nuclear proteins.

    abstract：:The fate of plasma and nuclear membrane polypeptides in preparations of acidic chromosomal protein from chicken erythrocytes has been investigated. It is shown that detergent extraction procedures (Nonidet P-40, Triton X-100, and saponin), commonly employed in the preparation of acidic chromosomal protein, cannot be r...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00670a034

    authors： Jackson RC

    更新日期：1976-12-14 00:00:00

  • SERPINB12 Is a Slow-Binding Inhibitor of Granzyme A and Hepsin.

    abstract：:The clade B/intracellular serpins protect cells from peptidase-mediated injury by forming covalent complexes with their targets. SERPINB12 is expressed in most tissues, especially at cellular interfaces with the external environment. This wide tissue distribution pattern is similar to that of granzyme A (GZMA). Becaus...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/acs.biochem.5b01042

    authors： Niehaus JZ,Miedel MT,Good M,Wyatt AN,Pak SC,Silverman GA,Luke CJ

    更新日期：2015-11-17 00:00:00

  • Structural, dynamic, and chemical characterization of a novel S-glycosylated bacteriocin.

    abstract：:Bacteriocins are bacterial peptides with specific activity against competing species. They hold great potential as natural preservatives and for their probiotic effects. We show here nuclear magnetic resonance-based evidence that glycocin F, a 43-amino acid bacteriocin from Lactobacillus plantarum, contains two β-link...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi200217u

    authors： Venugopal H,Edwards PJ,Schwalbe M,Claridge JK,Libich DS,Stepper J,Loo T,Patchett ML,Norris GE,Pascal SM

    更新日期：2011-04-12 00:00:00

  • Identification of c-di-GMP derivatives resistant to an EAL domain phosphodiesterase.

    abstract：:The bacterial second messenger signaling molecule bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) controls important biological processes such as biofilm formation, virulence response, and motility. This second messenger is sensed by macromolecular targets inside the cell, both protein and RNA, which ind...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi301510v

    authors： Shanahan CA,Gaffney BL,Jones RA,Strobel SA

    更新日期：2013-01-15 00:00:00

  • The SH2 domains of inositol polyphosphate 5-phosphatases SHIP1 and SHIP2 have similar ligand specificity but different binding kinetics.

    abstract：:SH2 domain-containing inositol 5-phosphatases 1 (SHIP1) and 2 (SHIP2) are structurally similar proteins that catalyze the degradation of lipid secondary messenger phosphatidylinositol 3,4,5-triphosphate to produce phosphatidylinositol 3,4-diphosphate. Despite their high sequence identity (51%), SHIP1 and SHIP2 share l...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi9012462

    authors： Zhang Y,Wavreille AS,Kunys AR,Pei D

    更新日期：2009-11-24 00:00:00

  • X-ray crystallographic and biochemical characterization of the inhibitory action of an imidazole-dioxolane compound on heme oxygenase.

    abstract：:Heme oxygenase (HO) catalyzes the regiospecific cleavage of the porphyrin ring of heme using reducing equivalents and O2 to produce biliverdin, iron, and CO. Because CO has a cytoprotective effect through the p38-MAPK pathway, HO is a potential therapeutic target in cancer. In fact, inhibition of the HO isoform HO-1 r...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi062264p

    authors： Sugishima M,Higashimoto Y,Oishi T,Takahashi H,Sakamoto H,Noguchi M,Fukuyama K

    更新日期：2007-02-20 00:00:00

  • The very low- and intermediate-density lipoprotein fraction isolated from apolipoprotein E-knockout mice transforms macrophages to foam cells through an apolipoprotein E-independent pathway.

    abstract：:Apolipoprotein E (apoE)-knockout mice develop severe atherosclerosis associated with high levels of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) in plasma. To investigate the atherogenic role of VLDL and IDL, the lipoprotein fraction containing both VLDL and IDL (apoEko-VLDL/IDL) was ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi980762v

    authors： Hakamata H,Sakaguchi H,Zhang C,Sakashita N,Suzuki H,Miyazaki A,Takeya M,Takahashi K,Kitamura N,Horiuchi S

    更新日期：1998-09-29 00:00:00

  • Influence of aggregation propensity and stability on amyloid fibril formation as studied by Fourier transform infrared spectroscopy and two-dimensional COS analysis.

    abstract：:Understanding the process of amyloidogenesis is important for the future treatment of misfolding-based diseases, such as Alzheimer's, spongiform encephalopathies, and other important disorders affecting humans. In this work, we have used one of the best-characterized models for folding and misfolding, the activation d...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi900960s

    authors： Cerdà-Costa N,De la Arada I,Avilés FX,Arrondo JL,Villegas S

    更新日期：2009-11-10 00:00:00

  • Conformational adaptation of apolipoprotein A-I to discretely sized phospholipid complexes.

    abstract：:The conformational constraints for apoA-I bound to recombinant phospholipid complexes (rHDL) were attained from a combination of chemical cross-linking and mass spectrometry. Molecular distances were then used to refine models of lipid-bound apoA-I on both 80 and 96 A diameter rHDL particles. To obtain molecular const...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi700384t

    authors： Bhat S,Sorci-Thomas MG,Tuladhar R,Samuel MP,Thomas MJ

    更新日期：2007-07-03 00:00:00

  • Aromatic substrate specificity of horseradish peroxidase C studied by a combined fluorescence line narrowing/energy minimization approach: the effect of localized side-chain reorganization.

    abstract：:Horseradish peroxidase C binds a wide variety of small H-donor compounds such as benzohydroxamic acid (BHA) and 2-naphthohydroxamic acid (NHA). In this work, we use the Mg(II)-mesoporphyrin prosthetic group derivative as a spectroscopic probe of the active site and of the interaction with the substrates. We report on ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi002938a

    authors： Laberge M,Osvath S,Fidy J

    更新日期：2001-08-07 00:00:00

  • Tubulin-G protein association stabilizes GTP binding and activates GTPase: cytoskeletal participation in neuronal signal transduction.

    abstract：:It has been suggested that dimeric tubulin can participate in the signal transduction process through its association with the GTP-binding (G) proteins Gs and Gi1. Using the photoaffinity GTP analog, azidoanilido-GTP, it has been shown that the transfer of nucleotide from tubulin to G alpha s and G alpha i1 is the key...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00198a052

    authors： Roychowdhury S,Rasenick MM

    更新日期：1994-08-16 00:00:00

  • Local dynamics of the M13 major coat protein in different membrane-mimicking systems.

    abstract：:The local environment of the transmembrane and C-terminal domain of M13 major coat protein was probed by site-directed ESR spin labeling when the protein was introduced into three membrane-mimicking systems, DOPC vesicles, sodium cholate micelles, and SDS micelles. For this purpose, we have inserted unique cysteine re...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi961770j

    authors： Stopar D,Spruijt RB,Wolfs CJ,Hemminga MA

    更新日期：1996-12-03 00:00:00

  • Inhibitors of the molybdenum cofactor containing 4-hydroxybenzoyl-CoA reductase.

    abstract：:4-Hydroxybenzoyl-CoA reductase (4-HBCR) is a member of the xanthine oxidase (XO) family of molybdenum cofactor containing enzymes and catalyzes the irreversible removal of a phenolic hydroxy group by reduction, yielding benzoyl-CoA and water. In this work the effects of various activity modulating compounds were chara...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi800137v

    authors： Johannes J,Unciuleac MC,Friedrich T,Warkentin E,Ermler U,Boll M

    更新日期：2008-04-29 00:00:00

  • Single-amino acid substitutions alter the specificity and affinity of PDZ domains for their ligands.

    abstract：:PDZ domains are modular protein-protein interaction domains that bind to specific C-terminal sequences of membrane proteins and/or to other PDZ domains. Certain PDZ domains in PSD-95 and syntrophins interact with C-terminal peptide ligands and heterodimerize with the extended nNOS PDZ domain. The capacity to interact ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi001633t

    authors： Gee SH,Quenneville S,Lombardo CR,Chabot J

    更新日期：2000-11-28 00:00:00

  • Crystal Structures of Apo and Liganded 4-Oxalocrotonate Decarboxylase Uncover a Structural Basis for the Metal-Assisted Decarboxylation of a Vinylogous β-Keto Acid.

    abstract：:The enzymes in the catechol meta-fission pathway have been studied for more than 50 years in several species of bacteria capable of degrading a number of aromatic compounds. In a related pathway, naphthalene, a toxic polycyclic aromatic hydrocarbon, is fully degraded to intermediates of the tricarboxylic acid cycle by...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/acs.biochem.6b00050

    authors： Guimarães SL,Coitinho JB,Costa DM,Araújo SS,Whitman CP,Nagem RA

    更新日期：2016-05-10 00:00:00

  • The flavoprotein component of the Escherichia coli sulfite reductase: expression, purification, and spectral and catalytic properties of a monomeric form containing both the flavin adenine dinucleotide and the flavin mononucleotide cofactors.

    abstract：:The flavoprotein component (SiR-FP) of the sulfite reductase from Escherichia coli is an octamer containing one FAD and one FMN per polypeptide chain. SiR-FP60, a SiR-FP fragment starting with alanine-52, was overexpressed in E. coli and purified as a monomer. The N-terminal part of the native protein contains thus al...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi9728699

    authors： Zeghouf M,Fontecave M,Macherel D,Covès J

    更新日期：1998-04-28 00:00:00

  • 20-Iodo-14,15-epoxyeicosa-8(Z)-enoyl-3-azidophenylsulfonamide: photoaffinity labeling of a 14,15-epoxyeicosatrienoic acid receptor.

    abstract：:Endothelium-derived epoxyeicosatrienoic acids (EETs) relax vascular smooth muscle by activating potassium channels and causing membrane hyperpolarization. Recent evidence suggests that EETs act via a membrane binding site or receptor. To further characterize this binding site or receptor, we synthesized 20-iodo-14,15-...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi102070w

    authors： Chen Y,Falck JR,Manthati VL,Jat JL,Campbell WB

    更新日期：2011-05-10 00:00:00

  • Selective binding to polynucleotides of the hybrid intercalating groove binder bis(pyrrolecarboxamide)-oxazolopyridocarbazole: a molecular modeling study.

    abstract：:In order to further characterize the binding of the hybrid molecule NetOPC [bis(pyrrolecarboxamide)-oxazolopyridocarbazole conjugate] to double-stranded DNA, we have performed a molecular modeling study to investigate the binding modes of the complexes possibly formed between NetOPC and synthetic polynucleotides poly ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00172a018

    authors： Goulaouic H,Carteau S,Subra F,Mouscadet JF,Auclair C,Sun JS

    更新日期：1994-02-15 00:00:00

  • Binding of protein phosphatase 2A to the L-type calcium channel Cav1.2 next to Ser1928, its main PKA site, is critical for Ser1928 dephosphorylation.

    abstract：:The cAMP-dependent protein kinase (PKA) controls a large number of cellular functions. One critical PKA substrate in the brain and heart is the L-type Ca(2+) channel Ca(v)1.2, the activity of which is upregulated by PKA. The main PKA phosphorylation site is serine 1928 in the central pore forming alpha(1)1.2 subunit o...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi051593z

    authors： Hall DD,Feekes JA,Arachchige Don AS,Shi M,Hamid J,Chen L,Strack S,Zamponi GW,Horne MC,Hell JW

    更新日期：2006-03-14 00:00:00

  • Probing the mechanism of hamster arylamine N-acetyltransferase 2 acetylation by active site modification, site-directed mutagenesis, and pre-steady state and steady state kinetic studies.

    abstract：:Arylamine N-acetyltransferases (NATs) catalyze an acetyl group transfer from acetyl coenzyme A (AcCoA) to arylamines, hydrazines, and their N-hydroxylated arylamine metabolites. The recently determined three-dimensional structures of prokaryotic NATs have revealed a cysteine protease-like Cys-His-Asp catalytic triad, ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi0497244

    authors： Wang H,Vath GM,Gleason KJ,Hanna PE,Wagner CR

    更新日期：2004-06-29 00:00:00

  • Duplex oligodeoxyribonucleotides cross-linked by mitomycin C at a single site: synthesis, properties, and cross-link reversibility.

    abstract：:Oligodeoxyribonucleotides cross-linked by reductively activated mitomycin C (MC) were prepared and purified for the first time. The cross-linked products were structurally characterized by nucleoside and MC-nucleoside adduct analysis. Optimal conditions were established for the cross-linking reaction, resulting in hig...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00464a015

    authors： Borowy-Borowski H,Lipman R,Chowdary D,Tomasz M

    更新日期：1990-03-27 00:00:00

  • Analysis of peptides for helical prediction.

    abstract：:Two terminally blocked peptides, acetylAETAAAKFLRQHMamide and acetylAETSSSRYLRQHMamide, were obtained by solid-phase synthesis, purified by reversed-phase chromatography, and characterized by fast atom bombardment mass spectrometry. Both peptides were soluble in aqueous solutions and remained monomeric over the concen...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00427a048

    authors： Merutka G,Stellwagen E

    更新日期：1989-01-10 00:00:00