Zur Synthese von Human-Little-Gastrin-I und dessen Leucin-15-, Norleucin-15- und Methoxinin-15-Analoga

Moröder, Luis; Göhring, Walter; Nyfeler, R.; Scharf, Regina; Thamm, P.; Wendlberger, Gerhard

doi:10.1515/bchm2.1983.364.1.157

Cited by 33 publications

(11 citation statements)

References 8 publications

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“…To overcome the problems related to the dimerization of the sulfhydryl groups of cysteine and/or the formation of diastereoisomeric sulfoxides via the oxidation of the methionine thioether moiety, methionine and cysteine were replaced with isosteric norleucine (Nle) [56][57][58] and (S)-2-aminobutyric acid (Abu) [56] in the synthetic peptides, respectively. In addition, cysteine and methionine could negatively influence the cleavage of the protecting groups during the chemical synthesis and the subsequent peptide purification.…”

Section: Design Of Peptides For CD and Nmr Studiesmentioning

confidence: 99%

Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics

Karska

Graul

Sikorska

et al. 2019

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A B S T R A C TThe transporter associated with antigen processing (TAP) directly participates in the immune response as a key component of the cytosolic peptide to major histocompatibility complex (MHC) class I protein loading machinery. This makes TAP an important target for viruses avoiding recognition by CD8+ T lymphocytes. Its activity can be suppressed by the UL49.5 protein produced by bovine herpesvirus 1, although the mechanism of this inhibition has not been understood so far.Therefore, the main goal of our study was to investigate the 3D structure of bovine herpesvirus 1 -encoded UL49.5 protein. The final structure of the inhibitor was established using circular dichroism (CD), 2D nuclear magnetic resonance (NMR), and molecular dynamics (MD) in membrane mimetic environments. In NMR studies, UL49.5 was represented by two fragments: the extracellular region (residues 1-35) and the transmembraneintracellular fragment (residues 36-75), displaying various functions during viral invasion. After the empirical structure determination, a molecular docking procedure was used to predict the complex of UL49.5 with the TAP heterodimer.Our results revealed that UL49.5 adopted a highly flexible membrane-proximal helical structure in the extracellular part. In the transmembrane region, we observed two short α-helices. Furthermore, the cytoplasmic part had an unordered structure. Finally, we propose three different orientations of UL49.5 in the complex with TAP. Our studies provide, for the first time, the experimental structural information on UL49.5 and structurebased insight in its mechanism of action which might be helpful in designing new drugs against viral infections.

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Section: Design Of Peptides For CD and Nmr Studiesmentioning

confidence: 99%

Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics

Karska

Graul

Sikorska

et al. 2019

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…In the synthesis of bioactive peptides the facile oxidation of methionine to the sulfoxides, which generally is accompanied by a significant loss of bioactivity, has always been a matter of great concern. Efficient methods have been developed over the years for the quantitative reduction of methionine sulfoxides [10], but more suitable has proved to be the replacement of Met residues with leucine [11][12][13][14] and particularly with the isosteric norleucine [15], since bioactivities are usually retained almost quantitatively by the related peptide analogues. Similar to the positive experiences gained by the replacement of Met with Nle in bioactive peptides, substitution of even single methionine residues in semisynthetic proteins with the carba-analogue norleucine was without detectable effects on protein structure and function, as shown, for example, by ribonuclease S [16].…”

Section: Methionine and Related Analoguesmentioning

confidence: 99%

“…Enantiomeric resolution was achieved by deacylation of Ac-D,L-Mox-OH with hog renal acylase I. With this oxa-analogue a bypass to the problem of methionine sulfoxide formation was obtained, but the effects of Met replacements with Mox on the bioactivities of peptide hormones was found to vary from lowered to equal or even enhanced potencies compared with the wild-type peptide [15,[28][29][30]. These contrasting results may well be assigned to the reduced van der Waals radius of oxygen compared with sulfur, and to its higher electronegativity, and thus stronger tendency for hydrogen bonding.…”

Section: Methoxininementioning

confidence: 99%

Isosteric replacement of sulfur with other chalcogens in peptides and proteins

2005

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The review addresses the functional and structural properties of the two series of chalcogen analogues of amino acids in peptides and proteins, the methionine and the serine/cysteine series, and discusses the synthesis of the related selenium/tellurium analogues as well as their use in peptide synthesis and protein expression. Advances in synthetic methodologies and recombinant technologies and their combined applications in native and expressed protein ligation allows the isomorphous character of selenium- and tellurium-containing amino acids to be exploited for production of heavy metal mutants of proteins and thus to facilitate the phasing problem in x-ray crystallography. In addition, selenocysteine has been recognized as an ideal tool for the production of selenoenzymes with new catalytic activities. Moreover, the fully isomorphous character of disulfide replacement with diselenide is well suited to increase the robustness of cystine frameworks in cystine-rich peptides and proteins and for the de novo design of even non-native cystine frameworks by exploiting the highly negative redox potential of selenols.

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“…Preliminary investigations carried out on Nlell-HG-13 revealed that this hormone interacts strongly with calcium in trifluoroethanol (TFE), whereas no interaction has been observed in an aqueous ~o l u t i o n .~ In TFE the addition of calcium causes a substantial conformational change of the hormone from a folded to a disordered Biopolymers, Vol. 22,2443-2457(1983 structure. It has been found that two calcium ions per mole of hormone are involved in the complex.…”

Section: Introductionmentioning

confidence: 99%

Interaction of calcium ions with peptide hormones of the gastrin family

et al. 1983

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SynopsisThe interactions of Des-Trp1-Nlel2-minigastrin I (Nle"-HG-l3) and NleI5-little gastrin I (Nle'5-HG-17) with calcium ions have been investigated in water and in trifluoroethanol solution using uv and CD absorption techniques. Both hormones strongly interact with Ca2+ in the organic medium. In the case of Nlell-HG-13, the near-uv chiroptical properties (dominated by the transitions of the Trp residue in the C-terminal tetrapeptide sequence) indicate that three metal ions per mole of hormone are involved in the binding process. From the different response of near-uv and far-uv CD properties to the addition of calcium and from the change of the CD spectra in the aromatic absorption region, it is concluded that the biologically important C-terminal sequence is directly involved in the interaction with calcium.Elongation of the peptide chain from N1e"-HG-13 to Nle'5-HG-17 (NleI5-little gastrin I) does not provide any additional binding site for calcium ions. The change of the CD properties in the near-and far-uv indicates that three metal ions per mole of hormone are involved in the binding process. The dichroic absorption in the aromatic region indicates that only one of the two Trp residues of the little gastrin analog is sensitive to the presence of calcium. On the assumption that the variation of the CD properties is proportional to the extent of calcium binding, the binding constants K1, Kz, and K3 have been estimated roughly. Two similar sets of binding constants have been found, with K 1 > 106M-' and Ks of the order of 105M-', indicating similar binding sites in the two hormones with high affinity for calcium ions.

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Zur Synthese von Human-Little-Gastrin-I und dessen Leucin-15-, Norleucin-15- und Methoxinin-15-Analoga

Cited by 33 publications

References 8 publications

Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics

Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics

Isosteric replacement of sulfur with other chalcogens in peptides and proteins

Interaction of calcium ions with peptide hormones of the gastrin family

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