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      Nascent peptide assists the ribosome in recognizing chemically distinct small molecules


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          Regulation of gene expression in response to the changing environment is critical for cell survival. For instance, binding of macrolide antibiotics to the ribosome promote the translation arrest at the leader ORFs ermCL and ermBL necessary for inducing antibiotic resistance genes ermC and ermB. Cladinose-containing macrolides, like erythromycin (ERY), but not ketolides e.g., telithromycin (TEL), arrest translation of ermCL, while either ERY or TEL stall ermBL translation. How the ribosome distinguishes between chemically similar small molecules is unknown.

          We show that single amino acid changes in the leader peptide switch the specificity of recognition of distinct molecules, triggering gene activation in response to only ERY, only TEL, to both antibiotics, or preventing stalling altogether. Thus, the ribosomal response to chemical signals can be modulated by minute changes in the nascent peptide, suggesting that protein sequences could have been optimized for rendering translation sensitive to environmental cues.

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          Most cited references37

          • Record: found
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          Is Open Access

          tRNAdb 2009: compilation of tRNA sequences and tRNA genes

          One of the first specialized collections of nucleic acid sequences in life sciences was the ‘compilation of tRNA sequences and sequences of tRNA genes’ (http://www.trna.uni-bayreuth.de). Here, an updated and completely restructured version of this compilation is presented (http://trnadb.bioinf.uni-leipzig.de). The new database, tRNAdb, is hosted and maintained in cooperation between the universities of Leipzig, Marburg, and Strasbourg. Reimplemented as a relational database, tRNAdb will be updated periodically and is searchable in a highly flexible and user-friendly way. Currently, it contains more than 12 000 tRNA genes, classified into families according to amino acid specificity. Furthermore, the implementation of the NCBI taxonomy tree facilitates phylogeny-related queries. The database provides various services including graphical representations of tRNA secondary structures, a customizable output of aligned or un-aligned sequences with a variety of individual and combinable search criteria, as well as the construction of consensus sequences for any selected set of tRNAs.
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            Flexible fitting of atomic structures into electron microscopy maps using molecular dynamics.

            A novel method to flexibly fit atomic structures into electron microscopy (EM) maps using molecular dynamics simulations is presented. The simulations incorporate the EM data as an external potential added to the molecular dynamics force field, allowing all internal features present in the EM map to be used in the fitting process, while the model remains fully flexible and stereochemically correct. The molecular dynamics flexible fitting (MDFF) method is validated for available crystal structures of protein and RNA in different conformations; measures to assess and monitor the fitting process are introduced. The MDFF method is then used to obtain high-resolution structures of the E. coli ribosome in different functional states imaged by cryo-EM.
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              Erythromycin resistance by ribosome modification.

              B Weisblum (1995)

                Author and article information

                Nat Chem Biol
                Nat. Chem. Biol.
                Nature chemical biology
                5 December 2017
                04 January 2016
                March 2016
                12 December 2017
                : 12
                : 3
                : 153-158
                [1 ]Center for Biomolecular Sciences, University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, IL 60607, USA
                [2 ]Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
                Author notes
                corresponding authors: Alexander S. Mankin: shura@ 123456uic.edu ; Nora Vázquez-Laslop: nvazquez@ 123456uic.edu

                current address: Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA


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