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Pesquisa : G02.111.570.820.709.600.750 [Categoria DeCS]
Referências encontradas : 392 [refinar]
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[PMID]:28455257
[Au] Autor:Narang SS; Shuaib S; Goyal B
[Ad] Endereço:Department of Chemistry, School of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib 140406, Punjab, India.
[Ti] Título:Molecular insights into the inhibitory mechanism of rifamycin SV against ß -microglobulin aggregation: A molecular dynamics simulation study.
[So] Source:Int J Biol Macromol;102:1025-1034, 2017 Sep.
[Is] ISSN:1879-0003
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic ß -microglobulin (ß m) protein around skeletal joints and bones. The small molecules that modulate ß m aggregation have been identified in vitro, however, the underlying inhibitory mechanism remain elusive. In the present study, molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of an antibiotic, rifamycin SV (C ) reported for its in vitro anti-aggregation activity against ß m. The molecular docking analysis highlight that C display hydrophobic contacts with residues in the aggregation prone region of ß m. MD simulations reveal enhanced structural stability of ß m in the presence of C . C inhibit the conformational transition of the C-terminal region of ß m from a ß-sheet to random coil conformation, which is reported for the initiation of fibrillogenesis of ß m. The results of the present study provide insight into the key interactions and underlying inhibitory mechanism of a small molecule against ß m aggregation that will help in the design and development of more potent, novel inhibitors of ß m aggregation.
[Mh] Termos MeSH primário: Simulação de Dinâmica Molecular
Agregados Proteicos/efeitos dos fármacos
Rifamicinas/farmacologia
Microglobulina-2 beta/química
[Mh] Termos MeSH secundário: Conformação Proteica em Folha beta
Estabilidade Proteica
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Aggregates); 0 (Rifamycins); 0 (beta 2-Microglobulin); DU69T8ZZPA (rifamycin SV)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:29410408
[Au] Autor:Kuncha SK; Mazeed M; Singh R; Kattula B; Routh SB; Sankaranarayanan R
[Ad] Endereço:CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500007, India.
[Ti] Título:A chiral selectivity relaxed paralog of DTD for proofreading tRNA mischarging in Animalia.
[So] Source:Nat Commun;9(1):511, 2018 02 06.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:D-aminoacyl-tRNA deacylase (DTD), a bacterial/eukaryotic trans-editing factor, removes D-amino acids mischarged on tRNAs and achiral glycine mischarged on tRNA . An invariant cross-subunit Gly-cisPro motif forms the mechanistic basis of L-amino acid rejection from the catalytic site. Here, we present the identification of a DTD variant, named ATD (Animalia-specific tRNA deacylase), that harbors a Gly-transPro motif. The cis-to-trans switch causes a "gain of function" through L-chiral selectivity in ATD resulting in the clearing of L-alanine mischarged on tRNA (G4•U69) by eukaryotic AlaRS. The proofreading activity of ATD is conserved across diverse classes of phylum Chordata. Animalia genomes enriched in tRNA (G4•U69) genes are in strict association with the presence of ATD, underlining the mandatory requirement of a dedicated factor to proofread tRNA misaminoacylation. The study highlights the emergence of ATD during genome expansion as a key event associated with the evolution of Animalia.
[Mh] Termos MeSH primário: Alanina/química
Aminoaciltransferases/química
Aminoacil-RNA de Transferência/química
Treonina/química
Aminoacilação de RNA de Transferência/genética
[Mh] Termos MeSH secundário: Alanina/genética
Alanina/metabolismo
Sequência de Aminoácidos
Aminoaciltransferases/genética
Aminoaciltransferases/metabolismo
Animais
Apicomplexa/genética
Apicomplexa/metabolismo
Bactérias/genética
Bactérias/metabolismo
Sítios de Ligação
Evolução Biológica
Clonagem Molecular
Cristalografia por Raios X
Expressão Gênica
Seres Humanos
Modelos Moleculares
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Aminoacil-RNA de Transferência/genética
Aminoacil-RNA de Transferência/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
Treonina/genética
Treonina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Transfer, Amino Acyl); 0 (Recombinant Proteins); 2ZD004190S (Threonine); EC 2.3.2.- (Aminoacyltransferases); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02204-w


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[PMID]:29374258
[Au] Autor:Hirata T; Mishra SK; Nakamura S; Saito K; Motooka D; Takada Y; Kanzawa N; Murakami Y; Maeda Y; Fujita M; Yamaguchi Y; Kinoshita T
[Ad] Endereço:Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
[Ti] Título:Identification of a Golgi GPI-N-acetylgalactosamine transferase with tandem transmembrane regions in the catalytic domain.
[So] Source:Nat Commun;9(1):405, 2018 01 26.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Many eukaryotic proteins are anchored to the cell surface via the glycolipid glycosylphosphatidylinositol (GPI). Mammalian GPIs have a conserved core but exhibit diverse N-acetylgalactosamine (GalNAc) modifications, which are added via a yet unresolved process. Here we identify the Golgi-resident GPI-GalNAc transferase PGAP4 and show by mass spectrometry that PGAP4 knockout cells lose GPI-GalNAc structures. Furthermore, we demonstrate that PGAP4, in contrast to known Golgi glycosyltransferases, is not a single-pass membrane protein but contains three transmembrane domains, including a tandem transmembrane domain insertion into its glycosyltransferase-A fold as indicated by comparative modeling. Mutational analysis reveals a catalytic site, a DXD-like motif for UDP-GalNAc donor binding, and several residues potentially involved in acceptor binding. We suggest that a juxtamembrane region of PGAP4 accommodates various GPI-anchored proteins, presenting their acceptor residue toward the catalytic center. In summary, we present insights into the structure of PGAP4 and elucidate the initial step of GPI-GalNAc biosynthesis.
[Mh] Termos MeSH primário: Acetilgalactosamina/química
Glicosilfosfatidilinositóis/química
Complexo de Golgi/metabolismo
N-Acetilgalactosaminiltransferases/química
[Mh] Termos MeSH secundário: Acetilgalactosamina/biossíntese
Motivos de Aminoácidos
Animais
Células CHO
Domínio Catalítico
Cricetulus
Cristalografia por Raios X
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Glicosilfosfatidilinositóis/metabolismo
Complexo de Golgi/ultraestrutura
Seres Humanos
Camundongos
Camundongos Knockout
Modelos Moleculares
Mutação
N-Acetilgalactosaminiltransferases/genética
N-Acetilgalactosaminiltransferases/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Homologia Estrutural de Proteína
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Glycosylphosphatidylinositols); EC 2.4.1.- (N-Acetylgalactosaminyltransferases); EC 2.4.1.41 (polypeptide N-acetylgalactosaminyltransferase); KM15WK8O5T (Acetylgalactosamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180128
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02799-0


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[PMID]:29374165
[Au] Autor:Evangelidis T; Nerli S; Novácek J; Brereton AE; Karplus PA; Dotas RR; Venditti V; Sgourakis NG; Tripsianes K
[Ad] Endereço:CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic.
[Ti] Título:Automated NMR resonance assignments and structure determination using a minimal set of 4D spectra.
[So] Source:Nat Commun;9(1):384, 2018 01 26.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Automated methods for NMR structure determination of proteins are continuously becoming more robust. However, current methods addressing larger, more complex targets rely on analyzing 6-10 complementary spectra, suggesting the need for alternative approaches. Here, we describe 4D-CHAINS/autoNOE-Rosetta, a complete pipeline for NOE-driven structure determination of medium- to larger-sized proteins. The 4D-CHAINS algorithm analyzes two 4D spectra recorded using a single, fully protonated protein sample in an iterative ansatz where common NOEs between different spin systems supplement conventional through-bond connectivities to establish assignments of sidechain and backbone resonances at high levels of completeness and with a minimum error rate. The 4D-CHAINS assignments are then used to guide automated assignment of long-range NOEs and structure refinement in autoNOE-Rosetta. Our results on four targets ranging in size from 15.5 to 27.3 kDa illustrate that the structures of proteins can be determined accurately and in an unsupervised manner in a matter of days.
[Mh] Termos MeSH primário: Algoritmos
Proteínas de Bactérias/química
Ressonância Magnética Nuclear Biomolecular/métodos
[Mh] Termos MeSH secundário: Modelos Moleculares
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Thermoanaerobacter/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180128
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02592-z


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[PMID]:29338043
[Au] Autor:Almeida VM; Frutuoso MA; Marana SR
[Ad] Endereço:Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
[Ti] Título:Search for independent (ß/α)4 subdomains in a (ß/α)8 barrel ß-glucosidase.
[So] Source:PLoS One;13(1):e0191282, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proteins that fold as (ß/α)8 barrels are thought to have evolved from half-barrels that underwent duplication and fusion events. The evidence is particularly clear for small barrels, which have almost identical halves. Additionally, computational calculations of the thermodynamic stability of these structures in the presence of denaturants have revealed that (ß/α)8 barrels contain two subunits or domains corresponding to half-barrels. Hence, within (ß/α)8 barrels, half-barrels are self-contained units. Here, we tested this hypothesis using ß-glucosidase from the bacterium Thermotoga maritima (bglTm), which has a (ß/α)8 barrel structure. Mutations were introduced to disrupt the noncovalent contacts between its halves and reveal the presence of two domains within bglTm, thus resulting in the creation of mutants T1 (containing W12A and I217A mutations) and T2 (containing W12A, H195A, I217A and F404A mutations). Mutants T1 and T2 were properly folded, as indicated by their fluorescence spectra and enzyme kinetic parameters. T1 and wild-type bglTm were equally stable, as shown by the results of thermal inactivation, differential scanning fluorimetry and guanidine hydrochloride denaturation experiments. However, T2 showed a first-order inactivation at 80°C, a single melting temperature of 82°C and only one transition concentration (c50) in 2.4 M guanidine hydrochloride. Additionally, T1 and T2 exhibited a cooperative denaturation process that followed a two-state model (m-values equal to 1.4 and 1.6 kcal/mol/M, respectively), similar to that of wild-type bglTm (1.2 kcal/mol/M). Hence, T1 and T2 each denatured as a single unit, although they contained different degrees of disruption between their halves. In conclusion, bglTm halves are equivalent in terms of their thermal and chemical stability; thus, their separate contributions to (ß/α)8 barrel unfolding cannot be disentangled.
[Mh] Termos MeSH primário: beta-Glucosidase/química
beta-Glucosidase/metabolismo
[Mh] Termos MeSH secundário: Ativação Enzimática
Cinética
Modelos Moleculares
Mutação
Conformação Proteica em Folha beta
Domínios Proteicos
Temperatura Ambiente
Thermotoga maritima/enzimologia
beta-Glucosidase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.2.1.21 (beta-Glucosidase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191282


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[PMID]:27773677
[Au] Autor:Jeronimo C; Langelier MF; Bataille AR; Pascal JM; Pugh BF; Robert F
[Ad] Endereço:Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
[Ti] Título:Tail and Kinase Modules Differently Regulate Core Mediator Recruitment and Function In Vivo.
[So] Source:Mol Cell;64(3):455-466, 2016 Nov 03.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mediator is a highly conserved transcriptional coactivator organized into four modules, namely Tail, Middle, Head, and Kinase (CKM). Previous work suggests regulatory roles for Tail and CKM, but an integrated model for these activities is lacking. Here, we analyzed the genome-wide distribution of Mediator subunits in wild-type and mutant yeast cells in which RNA polymerase II promoter escape is blocked, allowing detection of transient Mediator forms. We found that although all modules are recruited to upstream activated regions (UAS), assembly of Mediator within the pre-initiation complex is accompanied by the release of CKM. Interestingly, our data show that CKM regulates Mediator-UAS interaction rather than Mediator-promoter association. In addition, although Tail is required for Mediator recruitment to UAS, Tailless Mediator nevertheless interacts with core promoters. Collectively, our data suggest that the essential function of Mediator is mediated by Head and Middle at core promoters, while Tail and CKM play regulatory roles.
[Mh] Termos MeSH primário: Regulação Fúngica da Expressão Gênica
Complexo Mediador/genética
RNA Polimerase II/genética
Proteínas de Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/genética
Fator de Transcrição TFIIB/genética
[Mh] Termos MeSH secundário: Sítios de Ligação
Complexo Mediador/metabolismo
Modelos Moleculares
Regiões Promotoras Genéticas
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Subunidades Proteicas/genética
Subunidades Proteicas/metabolismo
RNA Polimerase II/metabolismo
Saccharomyces cerevisiae/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Fator de Transcrição TFIIB/metabolismo
Iniciação da Transcrição Genética
Ativação Transcricional
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mediator Complex); 0 (Protein Subunits); 0 (SUA7 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (Transcription Factor TFIIB); EC 2.7.7.- (RNA Polymerase II)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:27771988
[Au] Autor:Okimoto N; Suenaga A; Taiji M
[Ad] Endereço:a Laboratory for Computational Molecular Design, Computational Biology Research Core , Quantitative Biology Center (QBiC) , RIKEN, QBiC Building B, 6-2-4 Furuedai, Suita , Osaka 565-0874 , Japan.
[Ti] Título:Evaluation of protein-ligand affinity prediction using steered molecular dynamics simulations.
[So] Source:J Biomol Struct Dyn;35(15):3221-3231, 2017 Nov.
[Is] ISSN:1538-0254
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In computational drug design, ranking a series of compound analogs in a manner that is consistent with experimental affinities remains a challenge. In this study, we evaluated the prediction of protein-ligand binding affinities using steered molecular dynamics simulations. First, we investigated the appropriate conditions for accurate predictions in these simulations. A conic harmonic restraint was applied to the system for efficient sampling of work values on the ligand unbinding pathway. We found that pulling velocity significantly influenced affinity predictions, but that the number of collectable trajectories was less influential. We identified the appropriate pulling velocity and collectable trajectories for binding affinity predictions as 1.25 Å/ns and 100, respectively, and these parameters were used to evaluate three target proteins (FK506 binding protein, trypsin, and cyclin-dependent kinase 2). For these proteins using our parameters, the accuracy of affinity prediction was higher and more stable when Jarzynski's equality was employed compared with the second-order cumulant expansion equation of Jarzynski's equality. Our results showed that steered molecular dynamics simulations are effective for predicting the rank order of ligands; thus, they are a potential tool for compound selection in hit-to-lead and lead optimization processes.
[Mh] Termos MeSH primário: Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Sítios de Ligação
Domínio Catalítico
Quinase 2 Dependente de Ciclina/química
Ligantes
Ligação Proteica
Conformação Proteica em Folha beta
Proteínas de Ligação a Tacrolimo/química
Termodinâmica
Tripsina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); EC 3.4.21.4 (Trypsin); EC 5.2.1.- (Tacrolimus Binding Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161108
[St] Status:MEDLINE
[do] DOI:10.1080/07391102.2016.1251851


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[PMID]:28822812
[Au] Autor:Harris KL; Thomson RES; Strohmaier SJ; Gumulya Y; Gillam EMJ
[Ad] Endereço:School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia 4072, Australia.
[Ti] Título:Determinants of thermostability in the cytochrome P450 fold.
[So] Source:Biochim Biophys Acta;1866(1):97-115, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cytochromes P450 are found throughout the biosphere in a wide range of environments, serving a multitude of physiological functions. The ubiquity of the P450 fold suggests that it has been co-opted by evolution many times, and likely presents a useful compromise between structural stability and conformational flexibility. The diversity of substrates metabolized and reactions catalyzed by P450s makes them attractive starting materials for use as biocatalysts of commercially useful reactions. However, process conditions impose different requirements on enzymes to those in which they have evolved naturally. Most natural environments are relatively mild, and therefore most P450s have not been selected in Nature for the ability to withstand temperatures above ~40°C, yet industrial processes frequently require extended incubations at much higher temperatures. Thus, there has been considerable interest and effort invested in finding or engineering thermostable P450 systems. Numerous P450s have now been identified in thermophilic organisms and analysis of their structures provides information as to mechanisms by which the P450 fold can be stabilized. In addition, protein engineering, particularly by directed or artificial evolution, has revealed mutations that serve to stabilize particular mesophilic enzymes of interest. Here we review the current understanding of thermostability as it applies to the P450 fold, gleaned from the analysis of P450s characterized from thermophilic organisms and the parallel engineering of mesophilic forms for greater thermostability. We then present a perspective on how this information might be used to design stable P450 enzymes for industrial application. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Archaea/enzimologia
Bactérias/enzimologia
Sistema Enzimático do Citocromo P-450/química
Engenharia de Proteínas/métodos
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Archaea/genética
Bactérias/genética
Biocatálise
Estabilidade Enzimática
Expressão Gênica
Seres Humanos
Modelos Moleculares
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Dobramento de Proteína
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170821
[St] Status:MEDLINE


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[PMID]:28739446
[Au] Autor:Panneerselvam S; Shehzad A; Mueller-Dieckmann J; Wilmanns M; Bocola M; Davari MD; Schwaneberg U
[Ad] Endereço:HASYLAB, DESY, Notkestrasse 85, 22603 Hamburg, Germany.
[Ti] Título:Crystallographic insights into a cobalt (III) sepulchrate based alternative cofactor system of P450 BM3 monooxygenase.
[So] Source:Biochim Biophys Acta;1866(1):134-140, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:P450 BM3 is a multi-domain heme-containing soluble bacterial monooxygenase. P450 BM3 and variants are known to oxidize structurally diverse substrates. Crystal structures of individual domains of P450 BM3 are available. However, the spatial organization of the full-length protein is unknown. In this study, crystal structures of the P450 BM3 M7 heme domain variant with and without cobalt (III) sepulchrate are reported. Cobalt (III) sepulchrate acts as an electron shuttle in an alternative cofactor system employing zinc dust as the electron source. The crystal structure shows a binding site for the mediator cobalt (III) sepulchrate at the entrance of the substrate access channel. The mediator occupies an unusual position which is far from the active site and distinct from the binding of the natural redox partner (FAD/NADPH binding domain).
[Mh] Termos MeSH primário: Bacillus megaterium/química
Proteínas de Bactérias/química
Cobalto/química
Coenzimas/química
Sistema Enzimático do Citocromo P-450/química
Elétrons
Heme/química
NADPH-Ferri-Hemoproteína Redutase/química
NADP/química
[Mh] Termos MeSH secundário: Bacillus megaterium/enzimologia
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Domínio Catalítico
Clonagem Molecular
Cobalto/metabolismo
Coenzimas/metabolismo
Cristalografia por Raios X
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Heme/metabolismo
Modelos Moleculares
NADP/metabolismo
NADPH-Ferri-Hemoproteína Redutase/genética
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Especificidade por Substrato
Zinco/química
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Coenzymes); 0 (Recombinant Proteins); 3G0H8C9362 (Cobalt); 42VZT0U6YR (Heme); 53-59-8 (NADP); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase); EC 1.6.2.4 (flavocytochrome P450 BM3 monoxygenases); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:28734977
[Au] Autor:Castrignanò S; D'Avino S; Di Nardo G; Catucci G; Sadeghi SJ; Gilardi G
[Ad] Endereço:Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, Torino, Italy.
[Ti] Título:Modulation of the interaction between human P450 3A4 and B. megaterium reductase via engineered loops.
[So] Source:Biochim Biophys Acta;1866(1):116-125, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Chimerogenesis involving cytochromes P450 is a successful approach to generate catalytically self-sufficient enzymes. However, the connection between the different functional modules should allow a certain degree of flexibility in order to obtain functional and catalytically efficient proteins. We previously applied the molecular Lego approach to develop a chimeric P450 3A4 enzyme linked to the reductase domain of P450 BM3 (BMR). Three constructs were designed with the connecting loop containing no glycine, 3 glycine or 5 glycine residues and showed a different catalytic activity and coupling efficiency. Here we investigate how the linker affects the ability of P450 3A4 to bind substrates and inhibitors. We measure the electron transfer rates and the catalytic properties of the enzyme also in the presence of ketoconazole as inhibitor. The data show that the construct 3A4-5GLY-BMR with the longest loop better retains the binding ability and cooperativity for testosterone, compared to P450 3A4. In both 3A4-3GLY-BMR and 3A4-5GLY-BMR, the substrate induces an increase in the first electron transfer rate and a shorter lag phase related to a domain rearrangements, when compared to the construct without Gly. These data are consistent with docking results and secondary structure predictions showing a propensity to form helical structures in the loop of the 3A4-BMR and 3A4-3GLY-BMR. All three chimeras retain the ability to bind the inhibitor ketoconazole and show an IC comparable with those reported for the wild type protein. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Bacillus megaterium/genética
Proteínas de Bactérias/química
Inibidores do Citocromo P-450 CYP3A/química
Citocromo P-450 CYP3A/química
Cetoconazol/química
NADPH-Ferri-Hemoproteína Redutase/química
Proteínas Recombinantes de Fusão/química
[Mh] Termos MeSH secundário: Bacillus megaterium/enzimologia
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Citocromo P-450 CYP3A/genética
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/metabolismo
Expressão Gênica
Seres Humanos
Cetoconazol/metabolismo
Cinética
Ligantes
Simulação de Acoplamento Molecular
NADPH-Ferri-Hemoproteína Redutase/antagonistas & inibidores
NADPH-Ferri-Hemoproteína Redutase/genética
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Engenharia de Proteínas
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Relação Estrutura-Atividade
Especificidade por Substrato
Testosterona/química
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Ligands); 0 (Recombinant Fusion Proteins); 3XMK78S47O (Testosterone); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170724
[St] Status:MEDLINE



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