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[PMID]:28460646
[Au] Autor:Markusic DM; Nichols TC; Merricks EP; Palaschak B; Zolotukhin I; Marsic D; Zolotukhin S; Srivastava A; Herzog RW
[Ad] Endereço:Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA. dmarkusic@ufl.edu.
[Ti] Título:Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models.
[So] Source:J Transl Med;15(1):94, 2017 May 01.
[Is] ISSN:1479-5876
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical studies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also identified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T lymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other strategies to reduce capsid antigen presentation are desirable. METHODS: We tested several engineered AAV capsids for factor IX (FIX) expression for the treatment of hemophilia B by hepatic gene transfer. These capsids lack potential phosphorylation or ubiquitination sites, or had been generated through molecular evolution. RESULTS: AAV2 capsids lacking either a single lysine residue or 3 tyrosine residues directed substantially higher coagulation FIX expression in mice compared to wild-type sequence or other mutations. In hemophilia B dogs, however, expression from the tyrosine-mutant vector was merely comparable to historical data on AAV2. Evolved AAV2-LiC capsid was highly efficient in hemophilia B mice but lacked efficacy in a hemophilia B dog. CONCLUSIONS: Several alternative strategies for capsid modification improve the in vivo performance of AAV vectors in hepatic gene transfer for correction of hemophilia. However, capsid optimization solely in mouse liver may not predict efficacy in other species and thus is of limited translational utility.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Dependovirus/genética
Fator IX/genética
Técnicas de Transferência de Genes
Engenharia Genética
[Mh] Termos MeSH secundário: Animais
Cães
Vetores Genéticos/metabolismo
Hemofilia B/genética
Hepatócitos/metabolismo
Fígado/metabolismo
Lisina/genética
Masculino
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Modelos Animais
Mutação/genética
Transdução Genética
Tirosina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
42HK56048U (Tyrosine); 9001-28-9 (Factor IX); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1186/s12967-017-1200-1


  2 / 12560 MEDLINE  
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[PMID]:28456575
[Au] Autor:Grzesik P; MacMath D; Henson B; Prasad S; Joshi P; Desai PJ
[Ad] Endereço:Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, Baltimore, MD, USA.
[Ti] Título:Incorporation of the Kaposi's sarcoma-associated herpesvirus capsid vertex-specific component (CVSC) into self-assembled capsids.
[So] Source:Virus Res;236:9-13, 2017 05 15.
[Is] ISSN:1872-7492
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Self-assembly of herpesvirus capsids can be accomplished in heterologous expression systems provided all six capsid proteins are present. We have demonstrated the assembly of icosahedral Kaposi's sarcoma-associated herpesvirus (KSHV) capsids in insect cells using the baculovirus expression system. Using this self-assembly system we investigated whether we could add additional capsid associated proteins and determine their incorporation into the assembled capsid. We chose the capsid vertex-specific component (CVSC) proteins encoded by open reading frames (ORFs) 19 and 32 to test this. This complex sits on the capsid vertex and is important for capsid maturation in herpesvirus-infected cells. Co-immunoprecipitation assays were used to initially confirm a bi-molecular interaction between ORF19 and ORF32. Both proteins also precipitated the triplex proteins of the capsid shell (ORF26 and ORF62) as well as the major capsid protein (ORF25). Capsid immunoprecipitation assays revealed the incorporation of ORF19 as well as ORF32 into assembled capsids. Similar experiments also showed that the incorporation of each protein occurred independent of the other. These studies reveal biochemically how the KSHV CVSC interacts with the capsid shell.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Herpesvirus Humano 8/fisiologia
Sarcoma de Kaposi/virologia
Proteínas Virais/metabolismo
Montagem de Vírus
[Mh] Termos MeSH secundário: Proteínas do Capsídeo/genética
Proteínas do Capsídeo/metabolismo
Herpesvirus Humano 8/genética
Seres Humanos
Fases de Leitura Aberta
Proteínas Virais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Capsid Proteins); 0 (Viral Proteins)
[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:170501
[St] Status:MEDLINE


  3 / 12560 MEDLINE  
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[PMID]:29197575
[Au] Autor:Dochi T; Akita A; Kishimoto N; Takamune N; Misumi S
[Ad] Endereço:Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
[Ti] Título:Trametinib suppresses HIV-1 replication by interfering with the disassembly of human immunodeficiency virus type 1 capsid core.
[So] Source:Biochem Biophys Res Commun;495(2):1846-1850, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our previous study showed that the phosphorylation of a highly conserved serine residue, Ser in the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein is promoted by virion-incorporated extracellular signal-regulated kinase 2 (ERK2) and required for proper peptidyl-prolyl isomerase (Pin1)-mediated uncoating. Interestingly, western blot analysis demonstrated that phosphorylated/activated mitogen-activated protein kinase kinase 1/2 (MEK1/2), the upstream activator of ERK2, as well as ERK2 are incorporated into virions. Here, we show that the MEK1/2 selective allosteric inhibitor Trametinib reduces HIV-1 infectivity via the decrease in virion-incorporated ERK2 phosphorylation. The treatment of chronic HIV-1-infected T-cell line, CEM/LAV-1 cells with Trametinib results in a decrease in ERK2 phosphorylation in the virions. The viruses have relatively low infectivity and impaired reverse transcription. Cell-based fate-of-capsid uncoating assay showed that the reduction in infectivity was caused by a functional impairment of the uncoating process. Furthermore, the viruses from Trametinib-treated CEM/LAV-1 cells also showed decreased reverse transcription efficiency and attenuated multiple rounds of replication in human peripheral blood mononuclear cells (PBMCs). Taken together, these findings suggest that Trametinib suppresses HIV-1 replication by abrogating the proper disassembly of CA core.
[Mh] Termos MeSH primário: Capsídeo/fisiologia
HIV-1/efeitos dos fármacos
HIV-1/fisiologia
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Piridonas/administração & dosagem
Pirimidinonas/administração & dosagem
Replicação Viral/efeitos dos fármacos
Replicação Viral/fisiologia
[Mh] Termos MeSH secundário: Capsídeo/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ativação Enzimática/efeitos dos fármacos
Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores
Fosforilação/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pyridones); 0 (Pyrimidinones); 33E86K87QN (trametinib); EC 2.7.11.24 (MAPK1 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE


  4 / 12560 MEDLINE  
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[PMID]:29235442
[Au] Autor:Li S; Erdemci-Tandogan G; van der Schoot P; Zandi R
[Ad] Endereço:Department of Physics and Astronomy, University of California, Riverside, CA 92521, United States of America.
[Ti] Título:The effect of RNA stiffness on the self-assembly of virus particles.
[So] Source:J Phys Condens Matter;30(4):044002, 2018 Jan 31.
[Is] ISSN:1361-648X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Under many in vitro conditions, some small viruses spontaneously encapsidate a single stranded (ss) RNA into a protein shell called the capsid. While viral RNAs are found to be compact and highly branched because of long distance base-pairing between nucleotides, recent experiments reveal that in a head-to-head competition between an ssRNA with no secondary or higher order structure and a viral RNA, the capsid proteins preferentially encapsulate the linear polymer! In this paper, we study the impact of genome stiffness on the encapsidation free energy of the complex of RNA and capsid proteins. We show that an increase in effective chain stiffness because of base-pairing could be the reason why under certain conditions linear chains have an advantage over branched chains when it comes to encapsidation efficiency. While branching makes the genome more compact, RNA base-pairing increases the effective Kuhn length of the RNA molecule, which could result in an increase of the free energy of RNA confinement, that is, the work required to encapsidate RNA, and thus less efficient packaging.
[Mh] Termos MeSH primário: Pareamento de Bases
Proteínas do Capsídeo/metabolismo
RNA Viral/química
Vírion/química
[Mh] Termos MeSH secundário: Capsídeo
Conformação de Ácido Nucleico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Capsid Proteins); 0 (RNA, Viral)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1088/1361-648X/aaa159


  5 / 12560 MEDLINE  
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[PMID]:29182522
[Au] Autor:Losdorfer Bozic A; Podgornik R
[Ad] Endereço:Department of Theoretical Physics, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia.
[Ti] Título:Varieties of charge distributions in coat proteins of ssRNA+ viruses.
[So] Source:J Phys Condens Matter;30(2):024001, 2018 Jan 17.
[Is] ISSN:1361-648X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A major part of the interactions involved in the assembly and stability of icosahedral, positive-sense single-stranded RNA (ssRNA+) viruses is electrostatic in nature, as can be inferred from the strong pH- and salt-dependence of their assembly phase diagrams. Electrostatic interactions do not act only between the capsid coat proteins (CPs), but just as often provide a significant contribution to the interactions of the CPs with the genomic RNA, mediated to a large extent by positively charged, flexible N-terminal tails of the CPs. In this work, we provide two clear and complementary definitions of an N-terminal tail of a protein, and use them to extract the tail sequences of a large number of CPs of ssRNA+ viruses. We examine the pH-dependent interplay of charge on both tails and CPs alike, and show that-in contrast to the charge on the CPs-the net positive charge on the N-tails persists even to very basic pH values. In addition, we note a limit to the length of the wild-type genomes of those viruses which utilize positively charged tails, when compared to viruses without charged tails and similar capsid size. At the same time, we observe no clear connection between the charge on the N-tails and the genome lengths of the viruses included in our study.
[Mh] Termos MeSH primário: Proteínas do Capsídeo
Capsídeo/química
Vírus de RNA/química
RNA/química
[Mh] Termos MeSH secundário: Modelos Moleculares
Eletricidade Estática
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Capsid Proteins); 63231-63-0 (RNA)
[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:171129
[St] Status:MEDLINE
[do] DOI:10.1088/1361-648X/aa9ded


  6 / 12560 MEDLINE  
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[PMID]:29219580
[Au] Autor:Erdemci-Tandogan G; Orland H; Zandi R
[Ad] Endereço:Department of Physics and Astronomy, University of California, Riverside, California 92521, USA.
[Ti] Título:RNA Base Pairing Determines the Conformations of RNA Inside Spherical Viruses.
[So] Source:Phys Rev Lett;119(18):188102, 2017 Nov 03.
[Is] ISSN:1079-7114
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many simple RNA viruses enclose their genetic material by a protein shell called the capsid. While the capsid structures are well characterized for most viruses, the structure of RNA inside the shells and the factors contributing to it remain poorly understood. We study the impact of base pairing on the conformations of RNA and find that it undergoes a swollen coil to globule continuous transition as a function of the strength of the pairing interaction. We also observe a first order transition and kink profile as a function of RNA length. All these transitions could explain the different RNA profiles observed inside viral shells.
[Mh] Termos MeSH primário: Capsídeo/química
Conformação de Ácido Nucleico
RNA Viral/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Viral)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1103/PhysRevLett.119.188102


  7 / 12560 MEDLINE  
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[PMID]:29220409
[Au] Autor:Mata CP; Luque D; Gómez-Blanco J; Rodríguez JM; González JM; Suzuki N; Ghabrial SA; Carrascosa JL; Trus BL; Castón JR
[Ad] Endereço:Department of Structure of Macromolecules, Centro Nacional de Biotecnología (CNB-CSIC), Campus Cantoblanco, Madrid, Spain.
[Ti] Título:Acquisition of functions on the outer capsid surface during evolution of double-stranded RNA fungal viruses.
[So] Source:PLoS Pathog;13(12):e1006755, 2017 Dec.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Unlike their counterparts in bacterial and higher eukaryotic hosts, most fungal viruses are transmitted intracellularly and lack an extracellular phase. Here we determined the cryo-EM structure at 3.7 Å resolution of Rosellinia necatrix quadrivirus 1 (RnQV1), a fungal double-stranded (ds)RNA virus. RnQV1, the type species of the family Quadriviridae, has a multipartite genome consisting of four monocistronic segments. Whereas most dsRNA virus capsids are based on dimers of a single protein, the ~450-Å-diameter, T = 1 RnQV1 capsid is built of P2 and P4 protein heterodimers, each with more than 1000 residues. Despite a lack of sequence similarity between the two proteins, they have a similar α-helical domain, the structural signature shared with the lineage of the dsRNA bluetongue virus-like viruses. Domain insertions in P2 and P4 preferential sites provide additional functions at the capsid outer surface, probably related to enzyme activity. The P2 insertion has a fold similar to that of gelsolin and profilin, two actin-binding proteins with a function in cytoskeleton metabolism, whereas the P4 insertion suggests protease activity involved in cleavage of the P2 383-residue C-terminal region, absent in the mature viral particle. Our results indicate that the intimate virus-fungus partnership has altered the capsid genome-protective and/or receptor-binding functions. Fungal virus evolution has tended to allocate enzyme activities to the virus capsid outer surface.
[Mh] Termos MeSH primário: Proteínas do Capsídeo/metabolismo
Capsídeo/metabolismo
Modelos Moleculares
Vírus de RNA/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Capsídeo/enzimologia
Capsídeo/ultraestrutura
Proteínas do Capsídeo/química
Proteínas do Capsídeo/genética
Sequência Conservada
Microscopia Crioeletrônica
Evolução Molecular
Imagem Tridimensional
Mutagênese Insercional
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Estabilidade Proteica
Vírus de RNA/enzimologia
Vírus de RNA/genética
Vírus de RNA/ultraestrutura
Alinhamento de Sequência
Homologia Estrutural de Proteína
Propriedades de Superfície
Vírion/enzimologia
Vírion/genética
Vírion/metabolismo
Vírion/ultraestrutura
Xylariales/virologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Capsid Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006755


  8 / 12560 MEDLINE  
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[PMID]:29260200
[Au] Autor:Reid CA; Ertel KJ; Lipinski DM
[Ad] Endereço:Department of Ophthalmology, Eye Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
[Ti] Título:Improvement of Photoreceptor Targeting via Intravitreal Delivery in Mouse and Human Retina Using Combinatory rAAV2 Capsid Mutant Vectors.
[So] Source:Invest Ophthalmol Vis Sci;58(14):6429-6439, 2017 Dec 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Effective intravitreal gene delivery to cells of the central retina (i.e., photoreceptors) would be of substantial benefit for treating patients with retinal diseases, such as achromatopsia, where retinal detachment from a subretinal may be harmful. Previous studies demonstrated that mutation of the recombinant adeno-associated virus (rAAV) capsid through introduction of peptide insertions or amino acid substitutions dramatically alters vector tropism. Herein, we evaluate the photoreceptor transduction efficiency of three rAAV2/2-based capsid mutant vectors: rAAV2/2[7m8], rAAV2/2[QuadYF+TV], and a chimeric vector incorporating both mutations (termed rAAV2/2[MAX]) following intravitreal delivery in mice. Furthermore, we evaluate the transduction efficiency of rAAV2/2[MAX] using explanted human central retinal samples to address clinical translatability. Methods: Vectors containing a GFP or mCherry reporter gene were intravitreally injected into C57BL/6J or Nrl-EGFP mice, respectively. Transduction was assessed in vivo utilizing a custom multiline confocal scanning laser ophthalmoscope. Injected Nrl-EGFP mouse retinas were used to quantify transduced photoreceptors using flow cytometry. Postmortem human retinal tissue was cultured following administration of rAAV2/2[MAX]. C57BL/6J retinas and human explants were cryosectioned to determine vector tropism. Results: The chimeric vector rAAV2/2[MAX] transduced significantly higher proportions of the retina than did either single mutant serotypes following intravitreal delivery in murine retina, including inner retinal cells and photoreceptors. Vector rAAV2[MAX] demonstrated transduction of human photoreceptors and ganglion cells. Conclusions: Transduction observed via rAAV2/2[MAX] indicates that combining mutations with complementary mechanisms of action in a single vector results in enhanced transduction. rAAV2/2[MAX] also presented the ability to transduce human photoreceptors and ganglion cells, indicating potential for efficient intravitreal vector delivery.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Dependovirus/genética
Técnicas de Transferência de Genes
Terapia Genética/métodos
Vetores Genéticos/administração & dosagem
Células Fotorreceptoras de Vertebrados/metabolismo
Retina/metabolismo
[Mh] Termos MeSH secundário: Animais
Dependovirus/fisiologia
Seres Humanos
Injeções Intravítreas
Camundongos
Camundongos Endogâmicos C57BL
Regiões Promotoras Genéticas/genética
Transdução Genética
Tropismo Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22281


  9 / 12560 MEDLINE  
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[PMID]:29095961
[Au] Autor:Koromyslova AD; Hansman GS
[Ad] Endereço:Schaller Research Group at the University of Heidelberg and the DKFZ, Heidelberg, Germany.
[Ti] Título:Nanobodies targeting norovirus capsid reveal functional epitopes and potential mechanisms of neutralization.
[So] Source:PLoS Pathog;13(11):e1006636, 2017 Nov.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Norovirus is the leading cause of gastroenteritis worldwide. Despite recent developments in norovirus propagation in cell culture, these viruses are still challenging to grow routinely. Moreover, little is known on how norovirus infects the host cells, except that histo-blood group antigens (HBGAs) are important binding factors for infection and cell entry. Antibodies that bind at the HBGA pocket and block attachment to HBGAs are believed to neutralize the virus. However, additional neutralization epitopes elsewhere on the capsid likely exist and impeding the intrinsic structural dynamics of the capsid could be equally important. In the current study, we investigated a panel of Nanobodies in order to probe functional epitopes that could trigger capsid rearrangement and/ or interfere with HBGA binding interactions. The precise binding sites of six Nanobodies (Nano-4, Nano-14, Nano-26, Nano-27, Nano-32, and Nano-42) were identified using X-ray crystallography. We showed that these Nanobodies bound on the top, side, and bottom of the norovirus protruding domain. The impact of Nanobody binding on norovirus capsid morphology was analyzed using electron microscopy and dynamic light scattering. We discovered that distinct Nanobody epitopes were associated with varied changes in particle structural integrity and assembly. Interestingly, certain Nanobody-induced capsid morphological changes lead to the capsid protein degradation and viral RNA exposure. Moreover, Nanobodies employed multiple inhibition mechanisms to prevent norovirus attachment to HBGAs, which included steric obstruction (Nano-14), allosteric interference (Nano-32), and violation of normal capsid morphology (Nano-26 and Nano-85). Finally, we showed that two Nanobodies (Nano-26 and Nano-85) not only compromised capsid integrity and inhibited VLPs attachment to HBGAs, but also recognized a broad panel of norovirus genotypes with high affinities. Consequently, Nano-26 and Nano-85 have a great potential to function as novel therapeutic agents against human noroviruses.
[Mh] Termos MeSH primário: Anticorpos Neutralizantes/farmacologia
Antivirais/farmacologia
Proteínas do Capsídeo/antagonistas & inibidores
Capsídeo/efeitos dos fármacos
Modelos Moleculares
Norovirus/efeitos dos fármacos
Anticorpos de Domínio Único/farmacologia
[Mh] Termos MeSH secundário: Anticorpos Neutralizantes/química
Anticorpos Neutralizantes/metabolismo
Afinidade de Anticorpos
Antivirais/química
Antivirais/metabolismo
Sítios de Ligação de Anticorpos
Ligação Competitiva
Antígenos de Grupos Sanguíneos/química
Antígenos de Grupos Sanguíneos/metabolismo
Capsídeo/química
Capsídeo/metabolismo
Capsídeo/ultraestrutura
Proteínas do Capsídeo/química
Proteínas do Capsídeo/metabolismo
Reações Cruzadas
Cristalografia por Raios X
Difusão Dinâmica da Luz
Epitopos
Cinética
Microscopia Eletrônica de Transmissão
Norovirus/química
Norovirus/metabolismo
Norovirus/ultraestrutura
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Anticorpos de Domínio Único/química
Anticorpos de Domínio Único/metabolismo
Termodinâmica
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (Antiviral Agents); 0 (Blood Group Antigens); 0 (Capsid Proteins); 0 (Epitopes); 0 (Single-Domain Antibodies)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171103
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006636


  10 / 12560 MEDLINE  
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[PMID]:29040325
[Au] Autor:Roganowicz MD; Komurlu S; Mukherjee S; Plewka J; Alam SL; Skorupka KA; Wan Y; Dawidowski D; Cafiso DS; Ganser-Pornillos BK; Campbell EM; Pornillos O
[Ad] Endereço:Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
[Ti] Título:TRIM5α SPRY/coiled-coil interactions optimize avid retroviral capsid recognition.
[So] Source:PLoS Pathog;13(10):e1006686, 2017 Oct.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Restriction factors are important components of intrinsic cellular defense mechanisms against viral pathogens. TRIM5α is a restriction factor that intercepts the incoming capsid cores of retroviruses such as HIV and provides an effective species-specific barrier to retroviral infection. The TRIM5α SPRY domain directly binds the capsid with only very weak, millimolar-level affinity, and productive capsid recognition therefore requires both TRIM5α dimerization and assembly of the dimers into a multivalent hexagonal lattice to promote avid binding. Here, we explore the important unresolved question of whether the SPRY domains are flexibly linked to the TRIM lattice or more precisely positioned to maximize avidity. Biochemical and biophysical experiments indicate that the linker segment connecting the SPRY domain to the coiled-coil domain adopts an α-helical fold, and that this helical portion mediates interactions between the two domains. Targeted mutations were generated to disrupt the putative packing interface without affecting dimerization or higher-order assembly, and we identified mutant proteins that were nevertheless deficient in capsid binding in vitro and restriction activity in cells. Our studies therefore support a model wherein substantial avidity gains during assembly-mediated capsid recognition by TRIM5α come in part from tailored spacing of tethered recognition domains.
[Mh] Termos MeSH primário: Capsídeo/imunologia
Proteínas de Transporte/química
Proteínas de Transporte/imunologia
Retroviridae/imunologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Modelos Moleculares
Estrutura Secundária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (TRIM5 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171018
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006686



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