Base de dados : MEDLINE
Pesquisa : B01.050.500.644.400.275 [Categoria DeCS]
Referências encontradas : 352 [refinar]
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[PMID]:28603989
[Au] Autor:Wu Y; Zhangsun D; Zhu X; Kaas Q; Zhangsun M; Harvey PJ; Craik DJ; McIntosh JM; Luo S
[Ad] Endereço:Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Lab for Marine Drugs of Haikou, Hainan University , Haikou, Hainan 570228 China.
[Ti] Título:α-Conotoxin [S9A]TxID Potently Discriminates between α3ß4 and α6/α3ß4 Nicotinic Acetylcholine Receptors.
[So] Source:J Med Chem;60(13):5826-5833, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:α3ß4 nAChRs have been implicated in various pathophysiological conditions. However, the expression profile of α3ß4 nAChRs and α6/α3ß4 nAChRs overlap in a variety of tissues. To distinguish between these two subtypes, we redesigned peptide 1 (α-conotoxin TxID), which inhibits α3ß4 and α6/α3ß4 nAChR subtypes. We systematically mutated 1 to evaluate analogue selectivity for α3ß4 vs α6/α3ß4 nAChRs expressed in Xenopus laevis oocytes. One analogue, peptide 7 ([S9A]TxID), had 46-fold greater potency for α3ß4 versus α6/α3ß4 nAChRs. Peptide 7 had IC s > 10 µM for other nAChR subtypes. Molecular dynamics simulations suggested that Ser-9 of TxID was involved in a weak hydrogen bond with ß4 Lys-81 in the α6ß4 binding site but not in the α3ß4 binding site. When Ser-9 was substituted by an Ala, this hydrogen bond interaction was disrupted. These results provide further molecular insights into the selectivity of 7 and provide a guide for designing ligands that block α3ß4 nAChRs.
[Mh] Termos MeSH primário: Conotoxinas/farmacologia
Antagonistas Nicotínicos/farmacologia
Receptores Nicotínicos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Conotoxinas/química
Caramujo Conus/química
Espectroscopia de Ressonância Magnética
Simulação de Dinâmica Molecular
Antagonistas Nicotínicos/química
Oócitos/metabolismo
Peptídeos/química
Peptídeos/farmacologia
Ratos
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Conotoxins); 0 (Nicotinic Antagonists); 0 (Peptides); 0 (Receptors, Nicotinic); 0 (nicotinic receptor alpha3beta4); 0 (nicotinic receptor alpha6)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00546


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[PMID]:28398099
[Au] Autor:Norton RS
[Ad] Endereço:a Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University , Parkville , Australia.
[Ti] Título:Enhancing the therapeutic potential of peptide toxins.
[So] Source:Expert Opin Drug Discov;12(6):611-623, 2017 Jun.
[Is] ISSN:1746-045X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Peptide toxins are potent and often exquisitely selective probes of the structure and function of ion channels and receptors, and as such are of significant interest to the pharmaceutical and biotech industries as both therapeutic leads and pharmacological tools. Their progression as clinical candidates, however, faces many of the challenges that are common to peptide drugs generally. Areas covered: The attributes of peptide toxins as therapeutic leads are outlined, as well as some of the limiting factors that have hampered the clinical development of many promising candidates. Strategies to overcome or circumvent these limitations are described, and their applications to peptide toxins from cone snails, sea anemones and scorpions are exemplified. Expert opinion: Peptide toxins have exceeded their promise as valuable pharmacological tools but have yet to yield the anticipated bounty of therapeutic leads. As the number of new peptides identified in venom transcriptomes and proteomes expands rapidly, screening approaches that capture those with genuine therapeutic potential are required, along with methods for enhancing the stability, pharmacokinetics and pharmacodynamics of these peptides.
[Mh] Termos MeSH primário: Desenho de Drogas
Descoberta de Drogas/métodos
Peptídeos/farmacologia
[Mh] Termos MeSH secundário: Animais
Venenos de Cnidários/isolamento & purificação
Venenos de Cnidários/farmacologia
Caramujo Conus/metabolismo
Seres Humanos
Venenos de Moluscos/isolamento & purificação
Venenos de Moluscos/farmacologia
Peptídeos/isolamento & purificação
Proteoma
Venenos de Escorpião/isolamento & purificação
Venenos de Escorpião/farmacologia
Escorpiões/metabolismo
Anêmonas-do-Mar/metabolismo
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cnidarian Venoms); 0 (Mollusk Venoms); 0 (Peptides); 0 (Proteome); 0 (Scorpion Venoms)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170412
[St] Status:MEDLINE
[do] DOI:10.1080/17460441.2017.1317243


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[PMID]:28238803
[Au] Autor:Echterbille J; Gilles N; Araóz R; Mourier G; Amar M; Servent D; De Pauw E; Quinton L
[Ad] Endereço:Laboratory of Mass Spectrometry- MolSys, Department of Chemistry, University of Liege, Liege, Belgium.
[Ti] Título:Discovery and characterization of EII a new α-conotoxin from Conus ermineus venom by nAChRs affinity capture monitored by MALDI-TOF/TOF mass spectrometry.
[So] Source:Toxicon;130:1-10, 2017 May.
[Is] ISSN:1879-3150
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Animal toxins are peptides that often bind with remarkable affinity and selectivity to membrane receptors such as nicotinic acetylcholine receptors (nAChRs). The latter are, for example, targeted by α-conotoxins, a family of peptide toxins produced by venomous cone snails. nAChRs are implicated in numerous physiological processes explaining why the design of new pharmacological tools and the discovery of potential innovative drugs targeting these receptor channels appear so important. This work describes a methodology developed to discover new ligands of nAChRs from complex mixtures of peptides. The methodology was set up by the incubation of Torpedo marmorata electrocyte membranes rich in nAChRs with BSA tryptic digests (>100 peptides) doped by small amounts of known nAChRs ligands (α-conotoxins). Peptides that bind to the receptors were purified and analyzed by MALDI-TOF/TOF mass spectrometry which revealed an enrichment of α-conotoxins in membrane-containing fractions. This result exhibits the binding of α-conotoxins to nAChRs. Negative controls were performed to demonstrate the specificity of the binding. The usefulness and the power of the methodology were also investigated for a discovery issue. The workflow was then applied to the screening of Conus ermineus crude venom, aiming at characterizing new nAChRs ligands from this venom, which has not been extensively investigated to date. The methodology validated our experiments by allowing us to bind two α-conotoxins (α-EI and α-EIIA) which have already been described as nAChRs ligands. Moreover, a new conotoxin, never described to date, was also captured, identified and sequenced from this venom. Classical pharmacology tests by radioligand binding using a synthetic homologue of the toxin confirm the activity of the new peptide, called α-EII . The K value of this peptide for Torpedo nicotinic receptors was measured at 2.2 ± 0.7 nM.
[Mh] Termos MeSH primário: Conotoxinas/isolamento & purificação
Receptores Nicotínicos/química
[Mh] Termos MeSH secundário: Animais
Conotoxinas/química
Caramujo Conus/química
Ligantes
Espectrometria de Massas/métodos
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Conotoxins); 0 (EII(B) conotoxin, Conus ermineus); 0 (Ligands); 0 (Receptors, Nicotinic)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170228
[St] Status:MEDLINE


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[PMID]:28223047
[Au] Autor:Degueldre M; Verdenaud M; Legarda G; Minambres R; Zuniga S; Leblanc M; Gilles N; Ducancel F; De Pauw E; Quinton L
[Ad] Endereço:Laboratory of Mass Spectrometry, MolSys, ULg, Liege, Belgium.
[Ti] Título:Diversity in sequences, post-translational modifications and expected pharmacological activities of toxins from four Conus species revealed by the combination of cutting-edge proteomics, transcriptomics and bioinformatics.
[So] Source:Toxicon;130:116-125, 2017 May.
[Is] ISSN:1879-3150
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Venomous animals have developed a huge arsenal of reticulated peptides for defense and predation. Based on various scaffolds, they represent a colossal pharmacological diversity, making them top candidates for the development of innovative drugs. Instead of relying on the classical, low-throughput bioassay-guided approach to identify innovative bioactive peptides, this work exploits a recent paradigm to access to venom diversity. This strategy bypasses the classical approach by combining high-throughput transcriptomics, proteomics and bioinformatics cutting-edge technologies to generate reliable peptide sequences. The strategy employed to generate hundreds of reliable sequences from Conus venoms is deeply described. The study led to the discovery of (i) conotoxins that belong to known pharmacological families targeting various GPCRs or ion-gated channels, and (ii) new families of conotoxins, never described to date. It also focusses on the diversity of genes, sequences, folds, and PTM's provided by such species.
[Mh] Termos MeSH primário: Venenos de Moluscos/química
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Animais
Cromatografia Líquida
Biologia Computacional/métodos
Caramujo Conus/metabolismo
Perfilação da Expressão Gênica
Venenos de Moluscos/metabolismo
Venenos de Moluscos/farmacologia
Filogenia
Isoformas de Proteínas
Proteômica/métodos
Análise de Sequência de RNA
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mollusk Venoms); 0 (Protein Isoforms)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170223
[St] Status:MEDLINE


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[PMID]:28215573
[Au] Autor:Lawler AJ; Duda TF
[Ad] Endereço:Museum of Zoology and Department of Ecology and Evolutionary Biology, University of Michigan, 1109 Geddes Avenue, Ann Arbor, MI 48109, USA. Electronic address: ajlawler@umich.edu.
[Ti] Título:Molecular and morphometric data suggest the presence of a neglected species in the marine gastropod family Conidae.
[So] Source:Mol Phylogenet Evol;109:421-429, 2017 Apr.
[Is] ISSN:1095-9513
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Knowledge concerning the taxonomic diversity of marine organisms is crucial for understanding processes associated with species diversification in geographic areas that are devoid of obvious barriers to dispersal. The marine gastropod family Conidae contains many species complexes due to lack of clear morphological distinctiveness and existence of morphological intergradations among described species. Conus flavidus Lamarck, 1810 and Conus frigidus Reeve, 1848 are currently recognized as distinct taxa, but are often difficult to distinguish by morphological characters and include several synonyms, including Conus peasei Brazier, 1877. C. peasei was originally described by Pease in 1861 (as Conus neglectus) based on slight morphological differences of a population of C. flavidus from Hawaii that distinguished it from C. flavidus from elsewhere. To evaluate the systematics of this group and specifically test the hypothesis of synonymy of C. peasei with C. flavidus, we examined molecular and morphometric data from specimens of C. flavidus, C. frigidus and C. peasei (i.e., C. flavidus from Hawaii). Multiple clades that contain individuals from particular geographic regions are apparent in gene trees constructed from sequences of a mitochondrial gene region. In particular, sequences of C. peasei cluster together separately from sequences of C. flavidus and C. frigidus. Although individuals of C. peasei, C. flavidus and C. frigidus each contain a unique set of alleles for a nuclear locus, a conotoxin gene, alleles of C. peasei are more similar to those of C. flavidus. In addition, sequences of a region of a second nuclear gene are identical among C. peasei and C. flavidus though they are distinct from sequences of C. frigidus. Morphometric data revealed that shells of C. peasei are distinct in some aspects, but are more similar to those of C. flavidus than to those of C. frigidus. Taken together, these results suggest that C. peasei represents a distinct species. Moreover, based on the contradictory relationships inferred from the mitochondrial and nuclear sequences (as well as morphometric data), C. peasei may have originated through past hybridization among the ancestral lineages that gave rise to C. flavidus and C. frigidus.
[Mh] Termos MeSH primário: Gastrópodes/genética
[Mh] Termos MeSH secundário: Animais
Conotoxinas/genética
Caramujo Conus/classificação
Gastrópodes/classificação
Genes Mitocondriais
Hawaii
Hibridização Genética
Filogenia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Conotoxins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE


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[PMID]:28152596
[Au] Autor:Vijayasarathy M; Basheer SM; Franklin JB; Balaram P
[Ad] Endereço:Molecular Biophysics Unit, Indian Institute of Science , Bangalore 560012, India.
[Ti] Título:Contryphan Genes and Mature Peptides in the Venom of Nine Cone Snail Species by Transcriptomic and Mass Spectrometric Analysis.
[So] Source:J Proteome Res;16(2):763-772, 2017 Feb 03.
[Is] ISSN:1535-3907
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The occurrence of contryphans, a class of single-disulfide-bond-containing peptides, is demonstrated by the analysis of the venom of nine species of cone snails. Ten full gene sequences and two partial gene sequences coding for contryphan precursor proteins have been identified by next-generation sequencing and compared with available sequences. The occurrence of mature peptides in isolated venom has been demonstrated by LC-ESI-MS/MS analysis. De novo sequencing of reduced, alkylated contryphans from C. frigidus and C. araneosus provides evidence of sequence variation and post-translational modification, notably gamma carboxylation of glutamic acid. The characterization of Fr965 (C. frigidus) provides a rare example of a sequence lacking Pro at position 5 in the disulfide loop. The widespread occurrence of contryphan genes and mature peptides in the venom of diverse cone snails is suggestive of their potential biological significance.
[Mh] Termos MeSH primário: Conotoxinas/genética
Peptídeos Cíclicos/genética
Transcriptoma/genética
Peçonhas/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos/genética
Animais
Conotoxinas/química
Caramujo Conus/química
Caramujo Conus/genética
Espectrometria de Massas
Peptídeos/química
Peptídeos/genética
Processamento de Proteína Pós-Traducional
Peçonhas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Conotoxins); 0 (Peptides); 0 (Peptides, Cyclic); 0 (Venoms); 0 (contryphan)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jproteome.6b00776


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[PMID]:27884878
[Au] Autor:Hong T; Park JE; Ling F; terBrugge KG; Tymianski M; Zhang HQ; Krings T
[Ad] Endereço:From the Department of Neurosurgery (T.H., F.L., H.Q.Z.), Xuanwu Hospital, Capital Medical University, Beijing, China.
[Ti] Título:Comparison of 3 Different Types of Spinal Arteriovenous Shunts below the Conus in Clinical Presentation, Radiologic Findings, and Outcomes.
[So] Source:AJNR Am J Neuroradiol;38(2):403-409, 2017 Feb.
[Is] ISSN:1936-959X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Spinal arteriovenous shunts below the conus constitute 3 types of lesions, which have previously been mainly described in case reports, given their rarity, and are sometimes misdiagnosed. The purpose of this study was to describe the features of each type and compare these types as to epidemiologic features, clinical and radiologic presentations, treatment, and outcomes in a consecutive series of 48 cases. MATERIALS AND METHODS: The prospectively collected data bases of 2 referral centers for spinal vascular lesions were retrospectively reviewed. Spinal arteriovenous shunts below the conus were defined as all dural and intradural shunts below the conus medullaris. Clinical features, radiologic findings, treatment results, and clinical outcomes were assessed. RESULTS: There were filum terminale arteriovenous fistulas in 11 patients (22.9%), radicular arteriovenous shunts in 7 patients (14.6%), and spinal dural arteriovenous fistulas in 30 patients (62.5%). Radicular arteriovenous shunts presented at a younger age ( = .017) and with a higher incidence of back pain symptoms ( = .037). A tethered spinal cord was found in 54.5% of patients with filum terminale arteriovenous fistulas and 23.3% of patients with spinal dural arteriovenous fistulas. After treatment, the angiographic complete obliteration rate was 89.4% and spinal function was improved significantly ( < .001). CONCLUSIONS: Three groups of spinal arteriovenous shunts below the conus can be differentiated according to clinical and radiologic features. Filum terminale arteriovenous fistulas are frequently associated with dysraphic malformations, which may suggest a particular embryologic origin.
[Mh] Termos MeSH primário: Derivação Arteriovenosa Cirúrgica/métodos
Coluna Vertebral/cirurgia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Fístula Arteriovenosa/diagnóstico por imagem
Fístula Arteriovenosa/cirurgia
Dor nas Costas/diagnóstico por imagem
Dor nas Costas/cirurgia
Cauda Equina/diagnóstico por imagem
Cauda Equina/cirurgia
Criança
Pré-Escolar
Caramujo Conus
Diagnóstico Diferencial
Dura-Máter/diagnóstico por imagem
Dura-Máter/cirurgia
Feminino
Seres Humanos
Imagem por Ressonância Magnética
Masculino
Meia-Idade
Defeitos do Tubo Neural/diagnóstico por imagem
Defeitos do Tubo Neural/cirurgia
Estudos Retrospectivos
Coluna Vertebral/diagnóstico por imagem
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161126
[St] Status:MEDLINE
[do] DOI:10.3174/ajnr.A5001


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[PMID]:27794464
[Au] Autor:Uribe JE; Puillandre N; Zardoya R
[Ad] Endereço:Museo Nacional de Ciencias Naturales (MNCN-CSIC), José Gutiérrez Abascal 2, 28006 Madrid, Spain.
[Ti] Título:Beyond Conus: Phylogenetic relationships of Conidae based on complete mitochondrial genomes.
[So] Source:Mol Phylogenet Evol;107:142-151, 2017 Feb.
[Is] ISSN:1095-9513
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Understanding how the extraordinary taxonomic and ecological diversity of cone snails (Caenogastropoda: Conidae) evolved requires a statistically robust phylogenetic framework, which thus far is not available. While recent molecular phylogenies have been able to distinguish several deep lineages within the family Conidae, including the genera Profundiconus, Californiconus, Conasprella, and Conus (and within this one, several subgenera), phylogenetic relationships among these genera remain elusive. Moreover, the possibility that additional deep lineages may exist within the family is open. Here, we reconstructed with probabilistic methods a molecular phylogeny of Conidae using the newly sequenced complete or nearly complete mitochondrial (mt) genomes of the following nine species that represent all main Conidae lineages and potentially new ones: Profundiconus teramachii, Californiconus californicus, Conasprella wakayamaensis, Lilliconus sagei, Pseudolilliconus traillii, Conus (Kalloconus) venulatus, Conus (Lautoconus) ventricosus, Conus (Lautoconus) hybridus, and Conus (Eugeniconus) nobilis. To test the monophyly of the family, we also sequenced the nearly complete mt genomes of the following three species representing closely related conoidean families: Benthomangelia sp. (Mangeliidae), Tomopleura sp. (Borsoniidae), and Glyphostoma sp. (Clathurellidae). All newly sequenced conoidean mt genomes shared a relatively constant gene order with rearrangements limited to tRNA genes. The reconstructed phylogeny recovered with high statistical support the monophyly of Conidae and phylogenetic relationships within the family. The genus Profundiconus was placed as sister to the remaining genera. Within these, a clade including Californiconus and Lilliconus+Pseudolilliconus was the sister group of Conasprella to the exclusion of Conus. The phylogeny included a new lineage whose relative phylogenetic position was unknown (Lilliconus) and uncovered thus far hidden diversity within the family (Pseudolilliconus). Moreover, reconstructed phylogenetic relationships allowed inferring that the peculiar diet of Californiconus based on worms, mollusks, crustaceans and fish is derived, and reinforce the hypothesis that the ancestor of Conidae was a worm hunter. A chronogram was reconstructed under an uncorrelated relaxed molecular clock, which dated the origin of the family shortly after the Cretaceous-Tertiary boundary (about 59million years ago) and the divergence among main lineages during the Paleocene and the Eocene (56-30million years ago).
[Mh] Termos MeSH primário: Caramujo Conus/classificação
Caramujo Conus/genética
Genoma Mitocondrial
Filogenia
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
DNA Mitocondrial/genética
Variação Genética
Mitocôndrias/genética
Análise de Sequência de DNA
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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[PMID]:27981829
[Au] Autor:Yuan Y; Balsara RD; Zajicek J; Kunda S; Castellino FJ
[Ad] Endereço:W. M. Keck Center for Transgene Research and ‡Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
[Ti] Título:Discerning the Role of the Hydroxyproline Residue in the Structure of Conantokin Rl-B and Its Role in GluN2B Subunit-Selective Antagonistic Activity toward N-Methyl-d-Aspartate Receptors.
[So] Source:Biochemistry;55(51):7112-7122, 2016 Dec 27.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Conantokins (con) are short γ-carboxyglutamate (Gla)-containing polypeptides expressed by marine snails that function as antagonists of N-methyl-d-aspartate receptor (NMDAR) ion channels. The Gla residues govern structural conformations and antagonistic activities of the conantokins. In addition to Gla, some conantokins, e.g., conRl-B, also contain a hydroxyproline (HyP or O) residue, which in this case is centrally located in the peptide at position 10. Because conRl-B specifically inhibits ion channels of GluN2B subunit-containing heterotetrameric NMDARs, we evaluated the unusual role of HyP in this effect. To accomplish this goal, we examined synthetic variants of conRl-B in which HyP was either deleted (conRl-B[ΔO ]) or replaced with alanine (conRl-B[O A]) or proline (conRl-B[O P]). The solution structures of these variants were determined by nuclear magnetic resonance spectroscopy. Deletion of HyP , or replacement of HyP with Ala , attenuated the distortion in the central region of the apo-conRl-B helix and allowed Mg -complexed end-to-end α-helix formation. The inhibitory properties of these variants were assessed by measuring NMDA/Gly-stimulated intracellular Ca influx in mice neurons. ConRl-B[O P] retained its NMDAR ion channel inhibitory activity in wild-type (WT) neurons but lost its GluN2B specificity, whereas conRl-B[ΔO ] showed overall diminished inhibitory function. ConRl-B[O A] showed attenuated inhibitory function but retained its GluN2B specificity. Thus, HyP plays a critical role in maintaining the structural integrity of conRl-B, which can be correlated with its GluN2B subunit-selective inhibition. Weakened inhibition by conRl-B was also observed in neurons lacking either the GluN2C or GluN2D subunit, compared to WT neurons. This suggests that GluN2C and GluN2D are also required for inhibition by conRl-B.
[Mh] Termos MeSH primário: Ácido 1-Carboxiglutâmico/química
Hidroxiprolina/química
Peptídeos/farmacologia
Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
[Mh] Termos MeSH secundário: Ácido 1-Carboxiglutâmico/genética
Ácido 1-Carboxiglutâmico/metabolismo
Alanina/química
Alanina/genética
Alanina/metabolismo
Sequência de Aminoácidos
Animais
Cálcio/metabolismo
Células Cultivadas
Caramujo Conus/química
Hidroxiprolina/genética
Hidroxiprolina/metabolismo
Espectroscopia de Ressonância Magnética
Camundongos Knockout
Modelos Moleculares
Mutação
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Neurônios/fisiologia
Peptídeos/química
Peptídeos/genética
Prolina/química
Prolina/genética
Prolina/metabolismo
Multimerização Proteica
Estrutura Secundária de Proteína
Receptores de N-Metil-D-Aspartato/química
Receptores de N-Metil-D-Aspartato/genética
Soluções
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NR2B NMDA receptor); 0 (Peptides); 0 (Receptors, N-Methyl-D-Aspartate); 0 (Solutions); 53445-96-8 (1-Carboxyglutamic Acid); 9DLQ4CIU6V (Proline); OF5P57N2ZX (Alanine); RMB44WO89X (Hydroxyproline); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170530
[Lr] Data última revisão:
170530
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b00962


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Fotocópia
[PMID]:27869701
[Au] Autor:Han P; Wang K; Dai X; Cao Y; Liu S; Jiang H; Fan C; Wu W; Chen J
[Ad] Endereço:College of Science, National University of Defense Technology, Changsha 410073, Hunan, China. hanpeng1021@126.com.
[Ti] Título:The Role of Individual Disulfide Bonds of µ-Conotoxin GIIIA in the Inhibition of Na 1.4.
[So] Source:Mar Drugs;14(11), 2016 Nov 18.
[Is] ISSN:1660-3397
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:µ-Conotoxin GIIIA, a peptide toxin isolated from , preferentially blocks the skeletal muscle sodium channel Na 1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to the blockade of Na 1.4, seven disulfide-deficient analogues were prepared and characterized, each with one, two, or three pairs of disulfide-bonded Cys residues replaced with Ala. The inhibitory potency of the analogues against Na 1.4 was assayed by whole cell patch-clamp on rNa 1.4, heterologously expressed in HEK293 cells. The corresponding IC values were 0.069 ± 0.005 µM for GIIIA, 2.1 ± 0.3 µM for GIIIA-1, 3.3 ± 0.2 µM for GIIIA-2, and 15.8 ± 0.8 µM for GIIIA-3 (-1, -2 and -3 represent the removal of disulfide bridges Cys3-Cys15, Cys4-Cys20 and Cys10-Cys21, respectively). Other analogues were not active enough for IC measurement. Our results indicate that all three disulfide bonds of GIIIA are required to produce effective inhibition of Na 1.4, and the removal of any one significantly lowers its sodium channel binding affinity. Cys10-Cys21 is the most important for the Na 1.4 potency.
[Mh] Termos MeSH primário: Conotoxinas/farmacologia
Caramujo Conus/metabolismo
Dissulfetos/metabolismo
Bloqueadores dos Canais de Sódio/farmacologia
Canais de Sódio/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Células HEK293
Seres Humanos
Músculo Esquelético/efeitos dos fármacos
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Conotoxins); 0 (Disulfides); 0 (Sodium Channel Blockers); 0 (Sodium Channels); 101484-15-5 (conotoxin GIII)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161122
[St] Status:MEDLINE



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