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1.
J Biol Chem ; 297(2): 100919, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34181950

RESUMO

Serum- and glucocorticoid-regulated kinase 3 (Sgk3) is a serine/threonine protein kinase activated by the phospholipid phosphatidylinositol 3-phosphate (PI3P) downstream of growth factor signaling via class I phosphatidylinositol 3-kinase (PI3K) signaling and by class III PI3K/Vps34-mediated PI3P production on endosomes. Upregulation of Sgk3 activity has recently been linked to a number of human cancers; however, the precise mechanism of activation of Sgk3 is unknown. Here, we use a wide range of cell biological, biochemical, and biophysical techniques, including hydrogen-deuterium exchange mass spectrometry, to investigate the mechanism of activation of Sgk3 by PI3P. We show that Sgk3 is regulated by a combination of phosphorylation and allosteric activation. We demonstrate that binding of Sgk3 to PI3P via its regulatory phox homology (PX) domain induces large conformational changes in Sgk3 associated with its activation and that the PI3P-binding pocket of the PX domain of Sgk3 is sequestered in its inactive conformation. Finally, we reconstitute Sgk3 activation via Vps34-mediated PI3P synthesis on phosphatidylinositol liposomes in vitro. In addition to identifying the mechanism of Sgk3 activation by PI3P, our findings open up potential therapeutic avenues in allosteric inhibitor development to target Sgk3 in cancer.

2.
Molecules ; 25(21)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182429

RESUMO

The current portfolio of organoselenium compounds applicable as volatile precursors for atomic layer deposition can be denoted as very limited. Hence, we report herein facile and cost-effective preparation of two bis(trialkylstannyl)selenides as well as one selenole and three bis(trialkylsilyl)selenides. Their syntheses have been optimized to: (i) use readily available and inexpensive starting materials, (ii) involve operationally simple methodology (heating in a pressure vessel), (iii) use a minimum amount of additives and catalysts, and (iv) either exclude additional purification or involve only simple distillation. The chemical structure of prepared Se derivatives was confirmed by multinuclear NMR and GC/MS. Their fundamental thermal properties were investigated by differential scanning calorimetry (DSC) and TGA methods that revealed thermal stability within the range of 160-300 °C.


Assuntos
Técnicas de Química Sintética/economia , Compostos Organosselênicos/síntese química , Compostos Orgânicos Voláteis/síntese química , Varredura Diferencial de Calorimetria , Catálise , Análise Custo-Benefício , Cromatografia Gasosa-Espectrometria de Massas , Chumbo/química , Espectroscopia de Ressonância Magnética , Compostos Organosselênicos/química , Oxigênio/química , Temperatura , Termogravimetria
3.
Chempluschem ; 85(3): 576-579, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32202391

RESUMO

Three cyclic silylselenides were prepared in a straightforward manner. Property tuning has been achieved by varying the ring size and the number of embedded selenium atoms. All silylselenides possess improved resistance towards moisture and oxidation as well as high thermal robustness and sufficient volatility with almost zero residues. The six-membered diselenide proved to be particularly superior Se precursors for atomic layer deposition and allowed facile preparation of MoSe2 layers. Their structure and composition have been investigated by Raman and X-ray photoelectron spectroscopy as well as scanning electron microscopy revealing vertically aligned flaky shaped nanosheets.

4.
Chemistry ; 25(69): 15779-15785, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31523878

RESUMO

A series of fluoroalkylated cyclic λ3 -iodanes and their hydrochloride salts was prepared and used in a combination with sodium ascorbate in buffer or aqueous methanol mixtures for radical fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan or its derivatives, and Trp residues in peptides. As demonstrated on several peptides, the aromatic amino acid residues of Trp, Tyr, Phe, and His are targeted with high selectivity to Trp. The functionalization method is biocompatible, mild, rapid, and transition-metal-free. The proteins myoglobin, ubiquitin, and human carbonic anhydrase I were also successfully functionalized.


Assuntos
Aminoácidos Aromáticos/química , Indóis/química , Peptídeos/química , Proteínas/química , Pirróis/química , Alquilação , Aminoácidos Aromáticos/síntese química , Radicais Livres/síntese química , Radicais Livres/química , Halogenação , Humanos , Indóis/síntese química , Modelos Moleculares , Peptídeos/síntese química , Proteínas/síntese química , Pirróis/síntese química
5.
Nucleic Acids Res ; 47(D1): D550-D558, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30357405

RESUMO

The Complex Portal (www.ebi.ac.uk/complexportal) is a manually curated, encyclopaedic database that collates and summarizes information on stable, macromolecular complexes of known function. It captures complex composition, topology and function and links out to a large range of domain-specific resources that hold more detailed data, such as PDB or Reactome. We have made several significant improvements since our last update, including improving compliance to the FAIR data principles by providing complex-specific, stable identifiers that include versioning. Protein complexes are now available from 20 species for download in standards-compliant formats such as PSI-XML, MI-JSON and ComplexTAB or can be accessed via an improved REST API. A component-based JS front-end framework has been implemented to drive a new website and this has allowed the use of APIs from linked services to import and visualize information such as the 3D structure of protein complexes, its role in reactions and pathways and the co-expression of complex components in the tissues of multi-cellular organisms. A first draft of the complete complexome of Saccharomyces cerevisiae is now available to browse and download.


Assuntos
Bases de Dados de Proteínas , Complexos Multiproteicos/química , Animais , Gráficos por Computador , Humanos , Substâncias Macromoleculares/química , Camundongos , Complexos Multiproteicos/metabolismo , Ácidos Nucleicos/química , Conformação Proteica
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