Conjugates of Amino Acids and Peptides with 5-O-Mycaminosyltylonolide and Their Interaction with the Ribosomal Exit Tunnel
| Autor: | Maxim S. Svetlov, Alexey A. Bogdanov, Andrey V. Golovin, G. I. Makarov, Nataliya V. Sumbatyan, Andrey G Tereshchenkov, Galina A. Korshunova, A. V. Shishkina |
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| Rok vydání: | 2013 |
| Předmět: |
Stereochemistry
Molecular Conformation Biomedical Engineering Pharmaceutical Science Bioengineering Peptide Molecular Dynamics Simulation Ribosome Luciferases Firefly Escherichia coli Protein biosynthesis Animals RNA Messenger Amino Acids Pharmacology chemistry.chemical_classification Binding Sites Chemistry Organic Chemistry Translation (biology) Ribosomal RNA Anti-Bacterial Agents Amino acid Folding (chemistry) Biochemistry Protein Biosynthesis Tylosin Peptides Ribosomes Biotechnology Conjugate |
| Zdroj: | Bioconjugate Chemistry. 24:1861-1869 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc400236n |
| Popis: | During protein synthesis the nascent polypeptide chain (NC) extends through the ribosomal exit tunnel (NPET). Also, the large group of macrolide antibiotics binds in the nascent peptide exit tunnel. In some cases interaction of NC with NPET leads to the ribosome stalling, a significant event in regulation of translation. In other cases NC-ribosome interactions lead to pauses in translation that play an important role in cotranslational folding of polypeptides emerging from the ribosome. The precise mechanism of NC recognition in NPET as well as factors that determine NC conformation in the ribosomal tunnel are unknown. A number of derivatives of the macrolide antibiotic 5-O-mycaminosyltylonolide (OMT) containing N-acylated amino acid or peptide residues were synthesized in order to study potential sites of NC-NPET interactions. The target compounds were prepared by conjugation of protected amino acids and peptides with the C23 hydroxyl group of the macrolide. These OMT derivatives showed high although varying abilities to inhibit the firefly luciferase synthesis in vitro. Three glycil-containing derivatives appeared to be strong inhibitors of translation, more potent than parental OMT. Molecular dynamics (MD) simulation of complexes of tylosin, OMT, and some of OMT derivatives with the large ribosomal subunit of E. coli illuminated a plausible reason for the high inhibitory activity of Boc-Gly-OMT. In addition, the MD study detected a new putative site of interaction of the nascent polypeptide chain with the NPET walls. |
| Databáze: | OpenAIRE |
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