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[PMID]: 29343704 [Au] Autor: Bachman AB; Keramisanou D; Xu W; Beebe K; Moses MA; Vasantha Kumar MV; Gray G; Noor RE; van der Vaart A; Neckers L; Gelis I [Ad] Endereço: Department of Chemistry, University of South Florida, Tampa, FL, 33620, USA. [Ti] Título: Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation. [So] Source: Nat Commun;9(1):265, 2018 01 17. [Is] ISSN: 2041-1723 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: During the Hsp90-mediated chaperoning of protein kinases, the core components of the machinery, Hsp90 and the cochaperone Cdc37, recycle between different phosphorylation states that regulate progression of the chaperone cycle. We show that Cdc37 phosphorylation at Y298 results in partial unfolding of the C-terminal domain and the population of folding intermediates. Unfolding facilitates Hsp90 phosphorylation at Y197 by unmasking a phosphopeptide sequence, which serves as a docking site to recruit non-receptor tyrosine kinases to the chaperone complex via their SH2 domains. In turn, Hsp90 phosphorylation at Y197 specifically regulates its interaction with Cdc37 and thus affects the chaperoning of only protein kinase clients. In summary, we find that by providing client class specificity, Hsp90 cochaperones such as Cdc37 do not merely assist in client recruitment but also shape the post-translational modification landscape of Hsp90 in a client class-specific manner. [Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo Chaperoninas/metabolismo Proteínas de Choque Térmico HSP90/metabolismo Proteínas Tirosina Quinases/metabolismo [Mh] Termos MeSH secundário: Seres Humanos Fosforilação Dobramento de Proteína Domínios de Homologia de src [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S. [Nm] Nome de substância: 0 (CDC37 protein, human); 0 (Cell Cycle Proteins); 0 (HSP90 Heat-Shock Proteins); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180119 [St] Status: MEDLINE [do] DOI: 10.1038/s41467-017-02711-w

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[PMID]: 29267381 [Au] Autor: Czemeres J; Buse K; Verkhivker GM [Ad] Endereço: Department of Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California, United States of America. [Ti] Título: Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: A mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains. [So] Source: PLoS One;12(12):e0190267, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A fundamental role of the Hsp90 and Cdc37 chaperones in mediating conformational development and activation of diverse protein kinase clients is essential in signal transduction. There has been increasing evidence that the Hsp90-Cdc37 system executes its chaperoning duties by recognizing conformational instability of kinase clients and modulating their folding landscapes. The recent cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex has provided a framework for dissecting regulatory principles underlying differentiation and recruitment of protein kinase clients to the chaperone machinery. In this work, we have combined atomistic simulations with protein stability and network-based rigidity decomposition analyses to characterize dynamic factors underlying allosteric mechanism of the chaperone-kinase cycle and identify regulatory hotspots that control client recognition. Through comprehensive characterization of conformational dynamics and systematic identification of stabilization centers in the unbound and client- bound Hsp90 forms, we have simulated key stages of the allosteric mechanism, in which Hsp90 binding can induce instability and partial unfolding of Cdk4 client. Conformational landscapes of the Hsp90 and Cdk4 structures suggested that client binding can trigger coordinated dynamic changes and induce global rigidification of the Hsp90 inter-domain regions that is coupled with a concomitant increase in conformational flexibility of the kinase client. This process is allosteric in nature and can involve reciprocal dynamic exchanges that exert global effect on stability of the Hsp90 dimer, while promoting client instability. The network-based rigidity analysis and emulation of thermal unfolding of the Cdk4-cyclin D complex and Hsp90-Cdc37-Cdk4 complex revealed weak spots of kinase instability that are present in the native Cdk4 structure and are targeted by the chaperone during client recruitment. Our findings suggested that this mechanism may be exploited by the Hsp90-Cdc37 chaperone to recruit and protect intrinsically dynamic kinase clients from degradation. The results of this investigation are discussed and interpreted in the context of diverse experimental data, offering new insights into mechanisms of chaperone regulation and binding. [Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo Chaperoninas/metabolismo Quinase 4 Dependente de Ciclina/metabolismo Proteínas de Choque Térmico HSP90/metabolismo [Mh] Termos MeSH secundário: Proteínas de Ciclo Celular/química Chaperoninas/química Proteínas de Choque Térmico HSP90/química Seres Humanos Simulação de Dinâmica Molecular Ligação Proteica Conformação Proteica Desdobramento de Proteína [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (CDC37 protein, human); 0 (Cell Cycle Proteins); 0 (HSP90 Heat-Shock Proteins); EC 2.7.11.22 (CDK4 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 4); EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180116 [Lr] Data última revisão: 180116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171222 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0190267

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[PMID]: 29059240 [Au] Autor: Takenaka T; Nakamura T; Yanaka S; Yagi-Utsumi M; Chandak MS; Takahashi K; Paul S; Makabe K; Arai M; Kato K; Kuwajima K [Ad] Endereço: Okazaki Institute for Integrative Bioscience and Institute for Molecular Science, National Institutes of Natural Sciences, Myodaiji, Okazaki, Aichi, Japan. [Ti] Título: Formation of the chaperonin complex studied by 2D NMR spectroscopy. [So] Source: PLoS One;12(10):e0187022, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We studied the interaction between GroES and a single-ring mutant (SR1) of GroEL by the NMR titration of 15N-labeled GroES with SR1 at three different temperatures (20, 25 and 30°C) in the presence of 3 mM ADP in 100 mM KCl and 10 mM MgCl2 at pH 7.5. We used SR1 instead of wild-type double-ring GroEL to precisely control the stoichiometry of the GroES binding to be 1:1 ([SR1]:[GroES]). Native heptameric GroES was very flexible, showing well resolved cross peaks of the residues in a mobile loop segment (residue 17-34) and at the top of a roof hairpin (Asn51) in the heteronuclear single quantum coherence spectra. The binding of SR1 to GroES caused the cross peaks to disappear simultaneously, and hence it occurred in a single-step cooperative manner with significant immobilization of the whole GroES structure. The binding was thus entropic with a positive entropy change (219 J/mol/K) and a positive enthalpy change (35 kJ/mol), and the binding constant was estimated at 1.9×105 M-1 at 25°C. The NMR titration in 3 mM ATP also indicated that the binding constant between GroES and SR1 increased more than tenfold as compared with the binding constant in 3 mM ADP. These results will be discussed in relation to the structure and mechanisms of the chaperonin GroEL/GroES complex. [Mh] Termos MeSH primário: Chaperoninas/química Espectroscopia de Ressonância Magnética/métodos [Mh] Termos MeSH secundário: Conformação Proteica Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171113 [Lr] Data última revisão: 171113 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171024 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0187022

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[PMID]: 28961247 [Au] Autor: Ke X; Zou W; Ren Y; Wang Z; Li J; Wu X; Zhao J [Ad] Endereço: State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, China. [Ti] Título: Functional divergence of chloroplast Cpn60α subunits during Arabidopsis embryo development. [So] Source: PLoS Genet;13(9):e1007036, 2017 Sep. [Is] ISSN: 1553-7404 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Chaperonins are a class of molecular chaperones that assist in the folding and assembly of a wide range of substrates. In plants, chloroplast chaperonins are composed of two different types of subunits, Cpn60α and Cpn60ß, and duplication of Cpn60α and Cpn60ß genes occurs in a high proportion of plants. However, the importance of multiple Cpn60α and Cpn60ß genes in plants is poorly understood. In this study, we found that loss-of-function of CPNA2 (AtCpn60α2), a gene encoding the minor Cpn60α subunit in Arabidopsis thaliana, resulted in arrested embryo development at the globular stage, whereas the other AtCpn60α gene encoding the dominant Cpn60α subunit, CPNA1 (AtCpn60α1), mainly affected embryonic cotyledon development at the torpedo stage and thereafter. Further studies demonstrated that CPNA2 can form a functional chaperonin with CPNB2 (AtCpn60ß2) and CPNB3 (AtCpn60ß3), while the functional partners of CPNA1 are CPNB1 (AtCpn60ß1) and CPNB2. We also revealed that the functional chaperonin containing CPNA2 could assist the folding of a specific substrate, KASI (ß-ketoacyl-[acyl carrier protein] synthase I), and that the KASI protein level was remarkably reduced due to loss-of-function of CPNA2. Furthermore, the reduction in the KASI protein level was shown to be the possible cause for the arrest of cpna2 embryos. Our findings indicate that the two Cpn60α subunits in Arabidopsis play different roles during embryo development through forming distinct chaperonins with specific AtCpn60ß to assist the folding of particular substrates, thus providing novel insights into functional divergence of Cpn60α subunits in plants. [Mh] Termos MeSH primário: Proteínas de Arabidopsis/metabolismo Arabidopsis/genética Chaperoninas/metabolismo Regulação da Expressão Gênica de Plantas Genes de Plantas [Mh] Termos MeSH secundário: 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/genética 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo Proteína de Transporte de Acila/genética Proteína de Transporte de Acila/metabolismo Sequência de Aminoácidos Arabidopsis/embriologia Arabidopsis/crescimento & desenvolvimento Proteínas de Arabidopsis/genética Chaperoninas/genética Cloroplastos/genética Cloroplastos/metabolismo Clonagem Molecular Cotilédone/embriologia Cotilédone/genética Duplicação Gênica Conformação Proteica Plântulas/embriologia Espectrometria de Massas em Tandem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Acyl Carrier Protein); 0 (Arabidopsis Proteins); EC 2.3.1.41 (3-Oxoacyl-(Acyl-Carrier-Protein) Synthase); EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170930 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pgen.1007036

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[PMID]: 28851842 [Au] Autor: Stiegler SC; Rübbelke M; Korotkov VS; Weiwad M; John C; Fischer G; Sieber SA; Sattler M; Buchner J [Ad] Endereço: From the Center for Integrated Protein Science Munich, Department of Chemistry, Technische Universität München, D-85747 Garching, Germany. [Ti] Título: A chemical compound inhibiting the Aha1-Hsp90 chaperone complex. [So] Source: J Biol Chem;292(41):17073-17083, 2017 Oct 13. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The eukaryotic Hsp90 chaperone machinery comprises many co-chaperones and regulates the conformation of hundreds of cytosolic client proteins. Therefore, it is not surprising that the Hsp90 machinery has become an attractive therapeutic target for diseases such as cancer. The compounds used so far to target this machinery affect the entire Hsp90 system. However, it would be desirable to achieve a more selective targeting of Hsp90-co-chaperone complexes. To test this concept, in this-proof-of-principle study, we screened for modulators of the interaction between Hsp90 and its co-chaperone Aha1, which accelerates the ATPase activity of Hsp90. A FRET-based assay that monitored Aha1 binding to Hsp90 enabled identification of several chemical compounds modulating the effect of Aha1 on Hsp90 activity. We found that one of these inhibitors can abrogate the Aha1-induced ATPase stimulation of Hsp90 without significantly affecting Hsp90 ATPase activity in the absence of Aha1. NMR spectroscopy revealed that this inhibitory compound binds the N-terminal domain of Hsp90 close to its ATP-binding site and overlapping with a transient Aha1-interaction site. We also noted that this inhibitor does not dissociate the Aha1-Hsp90 complex but prevents the specific interaction with the N-terminal domain of Hsp90 required for catalysis. In consequence, the inhibitor affected the activation and processing of Hsp90-Aha1-dependent client proteins We conclude that it is possible to abrogate a specific co-chaperone function of Hsp90 without inhibiting the entire Hsp90 machinery. This concept may also hold true for other co-chaperones of Hsp90. [Mh] Termos MeSH primário: Adenosina Trifosfatases/antagonistas & inibidores Chaperoninas/antagonistas & inibidores Inibidores Enzimáticos/química Proteínas de Choque Térmico HSP90/antagonistas & inibidores Complexos Multiproteicos/antagonistas & inibidores Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores Saccharomyces cerevisiae/química [Mh] Termos MeSH secundário: Adenosina Trifosfatases/química Adenosina Trifosfatases/metabolismo Chaperoninas/química Chaperoninas/genética Chaperoninas/metabolismo Proteínas de Choque Térmico HSP90/química Proteínas de Choque Térmico HSP90/genética Proteínas de Choque Térmico HSP90/metabolismo Complexos Multiproteicos/química Complexos Multiproteicos/genética Complexos Multiproteicos/metabolismo Ressonância Magnética Nuclear Biomolecular Domínios Proteicos Saccharomyces cerevisiae/genética Saccharomyces cerevisiae/metabolismo Proteínas de Saccharomyces cerevisiae/química Proteínas de Saccharomyces cerevisiae/genética Proteínas de Saccharomyces cerevisiae/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (AHA1 protein, S cerevisiae); 0 (Enzyme Inhibitors); 0 (HSP82 protein, S cerevisiae); 0 (HSP90 Heat-Shock Proteins); 0 (Multiprotein Complexes); 0 (Saccharomyces cerevisiae Proteins); EC 3.6.1.- (Adenosine Triphosphatases); EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171019 [Lr] Data última revisão: 171019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170831 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M117.797829

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[PMID]: 28837260 [Au] Autor: Rahnel H; Viht K; Lavogina D; Mazina O; Haljasorg T; Enkvist E; Uri A [Ad] Endereço: Institute of Chemistry, University of Tartu, Ravila 14A, 50411, Tartu, Estonia. [Ti] Título: A Selective Biligand Inhibitor of CK2 Increases Caspase-3 Activity in Cancer Cells and Inhibits Platelet Aggregation. [So] Source: ChemMedChem;12(20):1723-1736, 2017 Oct 20. [Is] ISSN: 1860-7187 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a K value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub-micromolar concentrations (EC =0.3 µm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development. [Mh] Termos MeSH primário: Antineoplásicos/síntese química Antineoplásicos/farmacologia Caseína Quinase II/antagonistas & inibidores Caspase 3/metabolismo Glicina/análogos & derivados Agregação Plaquetária/efeitos dos fármacos Tiazóis/síntese química Tiazóis/farmacologia [Mh] Termos MeSH secundário: Caseína Quinase II/metabolismo Caspase 3/genética Proteínas de Ciclo Celular/genética Proteínas de Ciclo Celular/metabolismo Chaperoninas/genética Chaperoninas/metabolismo Ativação Enzimática/efeitos dos fármacos Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Glicina/síntese química Glicina/farmacologia Células HeLa Seres Humanos Estrutura Molecular Fosforilação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ARC-772); 0 (Antineoplastic Agents); 0 (CDC37 protein, human); 0 (Cell Cycle Proteins); 0 (Thiazoles); EC 2.7.11.1 (Casein Kinase II); EC 3.4.22.- (Caspase 3); EC 3.6.1.- (Chaperonins); TE7660XO1C (Glycine) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171106 [Lr] Data última revisão: 171106 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170825 [St] Status: MEDLINE [do] DOI: 10.1002/cmdc.201700457

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[PMID]: 28784328 [Au] Autor: Verba KA; Agard DA [Ad] Endereço: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA. [Ti] Título: How Hsp90 and Cdc37 Lubricate Kinase Molecular Switches. [So] Source: Trends Biochem Sci;42(10):799-811, 2017 Oct. [Is] ISSN: 0968-0004 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The Hsp90/Cdc37 chaperone system interacts with and supports 60% of the human kinome. Not only are Hsp90 and Cdc37 generally required for initial folding, but many kinases rely on the Hsp90/Cdc37 throughout their lifetimes. A large fraction of these 'client' kinases are key oncoproteins, and their interactions with the Hsp90/Cdc37 machinery are crucial for both their normal and malignant activity. Recently, advances in single-particle cryo-electron microscopy (cryoEM) and biochemical strategies have provided the first key molecular insights into kinase-chaperone interactions. The surprising results suggest a re-evaluation of the role of chaperones in the kinase lifecycle, and suggest that such interactions potentially allow kinases to more rapidly respond to key signals while simultaneously protecting unstable kinases from degradation and suppressing unwanted basal activity. [Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo Chaperoninas/metabolismo Proteínas de Choque Térmico HSP90/metabolismo [Mh] Termos MeSH secundário: Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (CDC37 protein, human); 0 (Cell Cycle Proteins); 0 (HSP90 Heat-Shock Proteins); EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171011 [Lr] Data última revisão: 171011 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170809 [St] Status: MEDLINE

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[PMID]: 28711525 [Au] Autor: Li T; Chen X; Dai XY; Wei B; Weng QJ; Chen X; Ouyang DF; Yan R; Huang ZJ; Jiang HL; Zhu H; Lu JJ [Ad] Endereço: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. [Ti] Título: Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor. [So] Source: Toxicol Appl Pharmacol;330:65-73, 2017 Sep 01. [Is] ISSN: 1096-0333 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Heat shock protein 90 (Hsp90) is a critically conserved molecular chaperone protein and promising therapeutic target for cancer treatment. In this study, platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel Hsp90 inhibitor. We verified that PD did not affect the ATPase activity of Hsp90. However, PD disrupted the co-chaperone interaction of Hsp90/cell division cycle protein 37 (Cdc37) and subsequently degraded multiple Hsp90 client proteins without the feedback increase of Hsp70. In different genotypes of non-small cell lung cancer cells, co-treatment with the mTOR inhibitor Everolimus and PD enhanced antiproliferation activity and apoptotic effect. The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition. Our results not only identified PD as a novel Hsp90 inhibitor by disrupting the protein-protein interaction of Hsp90/Cdc37 complex, but also provided mechanistic insights into the ineffectiveness of mTOR inhibitors and identified therapeutic strategy for cancer treatment. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Proteínas de Ciclo Celular/efeitos dos fármacos Chaperoninas/efeitos dos fármacos Proteínas de Choque Térmico HSP90/antagonistas & inibidores Saponinas/toxicidade Serina-Treonina Quinases TOR/antagonistas & inibidores Triterpenos/toxicidade [Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico Carcinoma Pulmonar de Células não Pequenas/genética Proliferação Celular/efeitos dos fármacos Everolimo/farmacologia Seres Humanos Imunossupressores/farmacologia Neoplasias Pulmonares/tratamento farmacológico Neoplasias Pulmonares/genética Proteína Oncogênica v-akt/antagonistas & inibidores Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores Receptores de Somatomedina/antagonistas & inibidores [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (CDC37 protein, human); 0 (Cell Cycle Proteins); 0 (HSP90 Heat-Shock Proteins); 0 (IGF1R protein, human); 0 (Immunosuppressive Agents); 0 (Receptors, Somatomedin); 0 (Saponins); 0 (Triterpenes); 9HW64Q8G6G (Everolimus); CWJ06TA2GI (platycodin D); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Oncogene Protein v-akt); EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170814 [Lr] Data última revisão: 170814 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170717 [St] Status: MEDLINE

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[PMID]: 28489858 [Au] Autor: Niewieczerzal S; Sulkowska JI [Ad] Endereço: Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland. [Ti] Título: Knotting and unknotting proteins in the chaperonin cage: Effects of the excluded volume. [So] Source: PLoS One;12(5):e0176744, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Molecular dynamics simulations are used to explore the effects of chaperonin-like cages on knotted proteins with very low sequence similarity, different depths of a knot but with a similar fold, and the same type of topology. The investigated proteins are VirC2, DndE and MJ0366 with two depths of a knot. A comprehensive picture how encapsulation influences folding rates is provided based on the analysis of different cage sizes and temperature conditions. Neither of these two effects with regard to knotted proteins has been studied by means of molecular dynamics simulations with coarse-grained structure-based models before. We show that encapsulation in a chaperonin is sufficient to self-tie and untie small knotted proteins (VirC2, DndE), for which the equilibrium process is not accessible in the bulk solvent. Furthermore, we find that encapsulation reduces backtracking that arises from the destabilisation of nucleation sites, smoothing the free energy landscape. However, this effect can also be coupled with temperature rise. Encapsulation facilitates knotting at the early stage of folding and can enhance an alternative folding route. Comparison to unknotted proteins with the same fold shows directly how encapsulation influences the free energy landscape. In addition, we find that as the size of the cage decreases, folding times increase almost exponentially in a certain range of cage sizes, in accordance with confinement theory and experimental data for unknotted proteins. [Mh] Termos MeSH primário: Chaperoninas/metabolismo Modelos Moleculares Simulação de Dinâmica Molecular Dobramento de Proteína [Mh] Termos MeSH secundário: Temperatura Ambiente [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170911 [Lr] Data última revisão: 170911 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170511 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0176744

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[PMID]: 28482218 [Au] Autor: Wang L; Li L; Zhou ZH; Jiang ZY; You QD; Xu XL [Ad] Endereço: State Key Laboratory of Natural Medicines, Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. [Ti] Título: Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction. [So] Source: Eur J Med Chem;136:63-73, 2017 Aug 18. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules' key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC = 27 µM), a moderate binding capacity (K = 40 µM) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549 cell lines (IC = 26 µM, 15 µM and 38 µM respectively). All the data suggest that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Proteínas de Ciclo Celular/antagonistas & inibidores Chaperoninas/antagonistas & inibidores Proteínas de Choque Térmico HSP90/antagonistas & inibidores Bibliotecas de Moléculas Pequenas/farmacologia [Mh] Termos MeSH secundário: Antineoplásicos/síntese química Antineoplásicos/química Proteínas de Ciclo Celular/química Proliferação Celular/efeitos dos fármacos Chaperoninas/química Relação Dose-Resposta a Droga Avaliação Pré-Clínica de Medicamentos Ensaios de Seleção de Medicamentos Antitumorais Proteínas de Choque Térmico HSP90/química Seres Humanos Estrutura Molecular Ligação Proteica/efeitos dos fármacos Bibliotecas de Moléculas Pequenas/síntese química Bibliotecas de Moléculas Pequenas/química Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (CDC37 protein, human); 0 (Cell Cycle Proteins); 0 (HSP90 Heat-Shock Proteins); 0 (Small Molecule Libraries); EC 3.6.1.- (Chaperonins) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170928 [Lr] Data última revisão: 170928 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170509 [St] Status: MEDLINE

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