当前位置： SCI文献检索 > JOURNAL OF MOLECULAR BIOLOGY期刊下所有文献 > Ketoconazole-induced conformational changes in the active site of cytochrome P450eryF.

Ketoconazole-induced conformational changes in the active site of cytochrome P450eryF.

Abstract：

:The azole-based P450 inhibitor ketoconazole is used to treat fungal infections and functions by blocking ergosterol biosynthesis in yeast. Ketoconazole binds to mammalian P450 enzymes and this can result in drug-drug interactions and lead to liver damage. To identify protein-drug interactions that contribute to binding specificity and affinity, we determined the crystal structure of ketoconazole complexed with P450eryF. In the P450eryF/ketoconazole structure, the azole moiety and nearby rings of ketoconzole are positioned in the active site similar to the substrate, 6-deoxyerythronolide B, with the azole nitrogen atom coordinated to the heme iron atom. The remainder of the ketoconazole molecule extends into the active-site pocket, which is occupied by water in the substrate complex. Binding of ketoconazole led to unexpected conformational changes in the I-helix. The I-helix cleft near the active site has collapsed with a helical pitch of 5.4 A compared to 6.6 A in the substrate complex. P450eryF/ketoconazole crystals soaked in 6-deoxyerythronolide B to exchange ligands exhibit a structure identical with that of the original P450eryF/substrate complex, with the I-helix cleft restored to a pitch of 6.6 A. These findings indicate that the I-helix region of P450eryF is flexible and can adopt multiple conformations. An improved understanding of the flexibility of the active-site region of cytochrome P450 enzymes is important to gain insight into determinants of ligand binding/specificity as well as to evaluate models for catalytic mechanism based on static crystal structures.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Cupp-Vickery JR,Garcia C,Hofacre A,McGee-Estrada K

doi

10.1006/jmbi.2001.4803

keywords:

subject

Has Abstract

pub_date

2001-08-03 00:00:00

pages

101-10

issue

1

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(01)94803-X

journal_volume

311

pub_type

杂志文章

相关文献

JOURNAL OF MOLECULAR BIOLOGY文献大全
  • Translational and rotational diffusion of proteins.

    abstract：:We have investigated the translational and rotational diffusion of two proteins, bovine pancreatic trypsin inhibitor and hen egg white lysozyme, using molecular dynamics simulations in explicit solvent. The translational diffusion constants obtained from the simulations compare favourably with results from experiments...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.1994.1172

    authors： Smith PE,van Gunsteren WF

    更新日期：1994-02-18 00:00:00

  • High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs.

    abstract：:Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2010.05.024

    authors： Akif M,Georgiadis D,Mahajan A,Dive V,Sturrock ED,Isaac RE,Acharya KR

    更新日期：2010-07-16 00:00:00

  • The crystal structure of a sulfurtransferase from Azotobacter vinelandii highlights the evolutionary relationship between the rhodanese and phosphatase enzyme families.

    abstract：:Rhodanese is an ubiquitous enzyme that in vitro catalyses the transfer of a sulfur atom from suitable donors to nucleophilic acceptors by way of a double displacement mechanism. During the catalytic process the enzyme cycles between a sulfur-free and a persulfide-containing form, via formation of a persulfide linkage ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.2000.3651

    authors： Bordo D,Deriu D,Colnaghi R,Carpen A,Pagani S,Bolognesi M

    更新日期：2000-05-12 00:00:00

  • Dr. Jekyll and Mr. Hide: How Enterococcus faecalis Subverts the Host Immune Response to Cause Infection.

    abstract：:Enterococcus faecalis, a ubiquitous member of the healthy human gut microbiota, is also a common opportunistic pathogen and leading cause of nosocomial infections. This tenacious microbe is well adapted to infect and persist in multiple niches within the mammalian host and can rapidly tune its metabolism to respond to...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章,评审

    doi：10.1016/j.jmb.2019.05.030

    authors： Kao PHN,Kline KA

    更新日期：2019-07-26 00:00:00

  • Regulation of the Caenorhabditis elegans gut cysteine protease gene cpr-1: requirement for GATA motifs.

    abstract：:Expression of the Caenorhabditis elegans cysteine protease gene cpr-1 is regulated both spatially and temporally. In situ hybridisation and Northern blot analysis have shown that this gene is expressed exclusively in gut cells of all developmental stages except the embryo. We now show by transgenic transformation with...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.1998.2093

    authors： Britton C,McKerrow JH,Johnstone IL

    更新日期：1998-01-01 00:00:00

  • Exploring the regulation of tRNA distribution on the genomic scale.

    abstract：:Though up to 20% of the total RNA in bacterial cells is tRNA, the regulation of tRNA distribution on the genomic level remains unclear. tRNA distribution is governed by four processes: transcription, processing of precursor tRNA, degradation of precursor tRNA and degradation of mature tRNA. To elucidate the relationsh...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2004.01.024

    authors： Dittmar KA,Mobley EM,Radek AJ,Pan T

    更新日期：2004-03-12 00:00:00

  • Small-angle X-ray scattering and single-molecule FRET spectroscopy produce highly divergent views of the low-denaturant unfolded state.

    abstract：:The results of more than a dozen single-molecule Förster resonance energy transfer (smFRET) experiments suggest that chemically unfolded polypeptides invariably collapse from an expanded random coil to more compact dimensions as the denaturant concentration is reduced. In sharp contrast, small-angle X-ray scattering (...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2012.01.016

    authors： Yoo TY,Meisburger SP,Hinshaw J,Pollack L,Haran G,Sosnick TR,Plaxco K

    更新日期：2012-05-04 00:00:00

  • Negative Epistasis and Evolvability in TEM-1 β-Lactamase--The Thin Line between an Enzyme's Conformational Freedom and Disorder.

    abstract：:Epistasis is a key factor in evolution since it determines which combinations of mutations provide adaptive solutions and which mutational pathways toward these solutions are accessible by natural selection. There is growing evidence for the pervasiveness of sign epistasis--a complete reversion of mutational effects, ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2015.05.011

    authors： Dellus-Gur E,Elias M,Caselli E,Prati F,Salverda ML,de Visser JA,Fraser JS,Tawfik DS

    更新日期：2015-07-17 00:00:00

  • The rate of polyQ-mediated aggregation is dramatically affected by the number and location of surrounding domains.

    abstract：:The nine polyglutamine (polyQ) neurodegenerative diseases are caused in part by a gain-of-function mechanism involving protein misfolding, the deposition of β-sheet-rich aggregates and neuronal toxicity. While previous experimental evidence suggests that the polyQ-induced misfolding mechanism is context dependent, the...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2011.09.014

    authors： Robertson AL,Bate MA,Buckle AM,Bottomley SP

    更新日期：2011-11-04 00:00:00

  • Congruence of in vivo and in vitro insertion patterns in hot E. coli gene targets of transposable element Mu: opposing roles of MuB in target capture and integration.

    abstract：:Phage Mu transposes promiscuously, employing protein MuB for target capture. MuB forms stable filaments on A/T-rich DNA, and a correlation between preferred MuB binding and Mu integration has been observed. We have investigated the relationship between MuB-binding and Mu insertion into hot and cold Mu targets within t...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2008.05.032

    authors： Ge J,Harshey RM

    更新日期：2008-07-18 00:00:00

  • Topology of the components of the DNA packaging machinery in the phage phi29 prohead.

    abstract：:Chromosome condensation inside dsDNA viral particles is a complex process requiring the coordinated action of several viral components. The similarity of the process in different viral systems has led to the suggestion that there is a common underlying mechanism for DNA packaging, in which the portal vertex or connect...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.2000.3712

    authors： Ibarra B,Castón JR,Llorca O,Valle M,Valpuesta JM,Carrascosa JL

    更新日期：2000-05-19 00:00:00

  • Negatively stained 50 S ribosomal subunits of Escherichia coli.

    abstract：:Ribosomes are large nucleoproteins of approximately 3 X 10(6) Mr. In contrast to helical or spherical nucleoproteins (viruses) of similar size (which consist of several hundred small asymmetric units reproduced by symmetry), ribosomes are completely asymmetric; therefore, the amount of structural information (defined ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(86)90366-9

    authors： Hoppe W,Oettl H,Tietz HR

    更新日期：1986-11-20 00:00:00

  • Geometry of the flagellar motor in the cytoplasmic membrane of Salmonella typhimurium as determined by stereo-photogrammetry of quick-freeze deep-etch replica images.

    abstract：:The precise geometry of the flagellar basal structure anchored in the cytoplasmic membrane was determined by digital stereo-photogrammetry of the images captured by quick-freeze deep-etch replica electron microscopy. In order to examine the structure on the periplasmic side of the membrane, we analyzed the MS ring com...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.1996.0038

    authors： Katayama E,Shiraishi T,Oosawa K,Baba N,Aizawa S

    更新日期：1996-01-26 00:00:00

  • In crystallo capture of a Michaelis complex and product-binding modes of a bacterial phosphotriesterase.

    abstract：:The mechanism by which the binuclear metallophosphotriesterases (PTEs, E.C. 3.1.8.1) catalyse substrate hydrolysis has been extensively studied. The mu-hydroxo bridge between the metal ions has been proposed to be the initiating nucleophile in the hydrolytic reaction. In contrast, analysis of some biomimetic systems h...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2007.10.061

    authors： Jackson CJ,Foo JL,Kim HK,Carr PD,Liu JW,Salem G,Ollis DL

    更新日期：2008-02-01 00:00:00

  • The 5' ends of Escherichia coli lac mRNA.

    abstract：:We identified the predominant 5' ends of an mRNA in Escherichia coli to the exact nucleotides. There are four such ends of lac mRNA in fully induced cells. About 70% of the molecules have the reported major in vitro end, A-A-U-U-G (at +1), which is located 38 nucleotides before the A-U-G translation start. Another 15%...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(85)90342-0

    authors： Cannistraro VJ,Kennell D

    更新日期：1985-03-20 00:00:00

  • Beyond plasma membrane targeting: role of the MA domain of Gag in retroviral genome encapsidation.

    abstract：:The MA (matrix) domain of the retroviral Gag polyprotein plays several critical roles during virus assembly. Although best known for targeting the Gag polyprotein to the inner leaflet of the plasma membrane for virus budding, recent studies have revealed that MA also contributes to selective packaging of the genomic R...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章,评审

    doi：10.1016/j.jmb.2011.04.072

    authors： Parent LJ,Gudleski N

    更新日期：2011-07-22 00:00:00

  • Catabolite activator protein-induced DNA bending in transcription initiation.

    abstract：:We describe experiments that enable us to track the presence and direction of the DNA bend induced by Escherichia coli catabolite activator protein (CAP) through the intermediate stages of transcription initiation at the lac promoter. Transcriptional complexes examined were formed on superhelical templates to enhance ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(91)90562-k

    authors： Zinkel SS,Crothers DM

    更新日期：1991-05-20 00:00:00

  • Characterization of Warfarin Inhibition Kinetics Requires Stabilization of Intramembrane Vitamin K Epoxide Reductases.

    abstract：:Intramembrane enzymes are often difficult for biochemical characterization. Human vitamin K epoxide reductase (VKOR) is the target of warfarin. However, this intramembrane enzyme becomes insensitive to warfarin inhibition in vitro, preventing the characterization of inhibition kinetics for decades. Here we employ stru...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2020.05.009

    authors： Li S,Liu S,Yang Y,Li W

    更新日期：2020-08-21 00:00:00

  • A comparison of the pH, urea, and temperature-denatured states of barnase by heteronuclear NMR: implications for the initiation of protein folding.

    abstract：:The denatured states of barnase that are induced by urea, acid, and high temperature and acid have been assigned and characterised by high resolution heteronuclear NMR. The assignment was completed using a combination of triple-resonance and magnetisation-transfer methods. The latter was facilitated by selecting a sui...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.1995.0618

    authors： Arcus VL,Vuilleumier S,Freund SM,Bycroft M,Fersht AR

    更新日期：1995-11-24 00:00:00

  • Site-specific structural variations accompanying tubular assembly of the HIV-1 capsid protein.

    abstract：:The 231-residue capsid (CA) protein of human immunodeficiency virus type 1 (HIV-1) spontaneously self-assembles into tubes with a hexagonal lattice that is believed to mimic the surface lattice of conical capsid cores within intact virions. We report the results of solid-state nuclear magnetic resonance (NMR) measurem...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2013.12.021

    authors： Bayro MJ,Chen B,Yau WM,Tycko R

    更新日期：2014-03-06 00:00:00

  • Binding of fibulin-1 to nidogen depends on its C-terminal globular domain and a specific array of calcium-binding epidermal growth factor-like (EG) modules.

    abstract：:The calcium-binding basement membrane protein fibulin-1C was shown to bind nidogen in a calcium-dependent fashion. Fibulin-1C consists of small N (domain 1) and C-terminal (domain III) globular structures connected by a central rod (domain II) composed of nine epidermal growth factor (EG) modules, eight of which posse...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.1997.1244

    authors： Adam S,Göhring W,Wiedemann H,Chu ML,Timpl R,Kostka G

    更新日期：1997-09-19 00:00:00

  • Engineered Bacillus lentus subtilisins having altered flexibility.

    abstract：:The three-dimensional structures of engineered variants of Bacillus lentus subtilisin having increased enzymatic activity, K27R/N87S/V104Y/N123S/T274A (RSYSA) and N76D/N87S/S103A/V104I (DSAI), were determined by X-ray crystallography. In addition to identifying changes in atomic position we report a method that identi...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.1999.3033

    authors： Graycar T,Knapp M,Ganshaw G,Dauberman J,Bott R

    更新日期：1999-09-10 00:00:00

  • Mapping transition states of protein unfolding by protein engineering of ligand-binding sites.

    abstract：:We describe a method for probing the integrity and relative orientation of structural elements that are indirectly linked by ligands in protein complexes during protein folding. The effect of 3'-GMP on the rate constants of unfolding of wild-type barnase and several mutants has been studied. By comparing the rates of ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(91)80188-z

    authors： Sancho J,Meiering EM,Fersht AR

    更新日期：1991-10-05 00:00:00

  • Crystal structures of phosphotransferase system enzymes PtxB (IIB(Asc)) and PtxA (IIA(Asc)) from Streptococcus mutans.

    abstract：:Streptococcus mutans is the primary etiological agent of dental caries in man and other mammalian organisms. This bacterium metabolizes carbohydrates actively and thrives under anaerobic conditions by fermenting l-ascorbate (Asc) via the sga operon, which includes SgaT, PtxB, and PtxA. These three proteins are members...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2008.12.046

    authors： Lei J,Li LF,Su XD

    更新日期：2009-02-20 00:00:00

  • UTP-bound and Apo structures of a minimal RNA uridylyltransferase.

    abstract：:3'-Uridylylation of RNA is emerging as a phylogenetically widespread phenomenon involved in processing events as diverse as uridine insertion/deletion RNA editing in mitochondria of trypanosomes and small nuclear RNA (snRNA) maturation in humans. This reaction is catalyzed by terminal uridylyltransferases (TUTases), w...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2006.11.065

    authors： Stagno J,Aphasizheva I,Rosengarth A,Luecke H,Aphasizhev R

    更新日期：2007-02-23 00:00:00

  • Crystallization and preliminary crystallographic investigation of methanol dehydrogenase from Methylobacterium extorquens AM1.

    abstract：:Single crystals of methanol dehydrogenase (MDH) from Methylobacterium extorquens AM1 have been grown by the vapour diffusion method. These crystals diffract to beyond 2 A resolution and are suitable for X-ray crystallography. They belong to the orthorhombic space group P2(1)2(1)2(1) and have the following unit cell pa...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(92)90509-i

    authors： Ghosh M,Harlos K,Blake CC,Richardson I,Anthony C

    更新日期：1992-11-05 00:00:00

  • RNA Splicing: A New Paradigm in Host-Pathogen Interactions.

    abstract：:RNA splicing brings diversity to the eukaryotic proteome. Different spliced variants of a gene may differ in their structure, function, localization, and stability influencing protein stoichiometry and physiological outcomes. Alternate spliced variants of different genes are known to associate with various chronic pat...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章,评审

    doi：10.1016/j.jmb.2019.03.001

    authors： Chauhan K,Kalam H,Dutt R,Kumar D

    更新日期：2019-04-05 00:00:00

  • The crystal structure of Thermotoga maritima maltosyltransferase and its implications for the molecular basis of the novel transfer specificity.

    abstract：:Maltosyltransferase (MTase) from the hyperthermophile Thermotoga maritima represents a novel maltodextrin glycosyltransferase acting on starch and malto-oligosaccharides. It catalyzes the transfer of maltosyl units from alpha-1,4-linked glucans or malto-oligosaccharides to other alpha-1,4-linked glucans, malto-oligosa...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.2001.4944

    authors： Roujeinikova A,Raasch C,Burke J,Baker PJ,Liebl W,Rice DW

    更新日期：2001-09-07 00:00:00

  • Characterization of the structure and the amyloidogenic properties of the Josephin domain of the polyglutamine-containing protein ataxin-3.

    abstract：:Expansion of the polyglutamine (polyQ) region in the protein ataxin-3 is associated with spinocerebellar ataxia type 3, an inherited neurodegenerative disorder that belongs to the family of polyQ diseases. Increasing evidence indicates that protein aggregation and fibre formation play an important role in these pathol...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2004.09.065

    authors： Masino L,Nicastro G,Menon RP,Dal Piaz F,Calder L,Pastore A

    更新日期：2004-12-03 00:00:00

  • The major human structural IgE epitope of the Brazil nut allergen Ber e 1: a chimaeric and protein microarray approach.

    abstract：:A protein microarray system containing different dilutions of 77 related and non-related proteins was used to show that IgE from subjects allergic to Brazil nut specifically recognise the seed 2S albumin protein (Ber e 1). Further, correctly folded chimaeric 2S albumin proteins containing structural epitope replacemen...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2004.08.065

    authors： Alcocer MJ,Murtagh GJ,Wilson PB,Progias P,Lin J,Archer DB

    更新日期：2004-10-22 00:00:00