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Research ArticleArticle

Slow Sequential Conformational Changes in Escherichia coli Ribosomes Induced by Lincomycin: Kinetic Evidence

Sofia Kallia-Raftopoulos and Dimitrios L. Kalpaxis
Molecular Pharmacology November 1999, 56 (5) 1042-1046; DOI: https://doi.org/10.1124/mol.56.5.1042
Sofia Kallia-Raftopoulos
Laboratory of Biochemistry, School of Medicine, University of Patras, Patras, Greece
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Dimitrios L. Kalpaxis
Laboratory of Biochemistry, School of Medicine, University of Patras, Patras, Greece
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Abstract

In a cell-free system derived from Escherichia coli,lincomycin produces biphasic logarithmic time plots for inhibition of peptide-bond formation when puromycin is used as an acceptor substrate and AcPhe-tRNA as a donor substrate. In a previous study, initial slope analysis of the logarithmic time plots revealed that the encounter complex CI between the initiator ribosomal complex (C) and lincomycin (I) undergoes a slow isomerization to C*I. During this change, the bound AcPhe-tRNA and lincomycin are rearranged to also accommodate puromycin, and this may account for the mixed noncompetitive inhibition (K i* = 70 μM) established at higher concentrations of the drug. The above-mentioned effect was further investigated by analyzing the late phase of the logarithmic time plots. It was found that C*I complex reacts with a second molecule of I, giving C*I2 complex. However, the logarithmic time plots remain biphasic even at high concentrations of lincomycin, making possible the identification of another inhibition constantK i*′, which is equal to 18 μM. The simplest explanation of this finding is to assume the existence of a second isomerization step C*I2 ⇌ C*I2 ′, slowly equilibrated. The determination of K i*′ enables us to calculate the isomerization constant (K isom = 2.9) with the formula K i*′ =K i*/(1 + K isom). Our results suggest that whenever a fast and reversible interaction of lincomycin with the elongating ribosomal complex C occurs, the latter undergoes a slow isomerization, which may be the result of conformational changes induced by the drug.

Footnotes

    • Received April 14, 1999.
    • Accepted August 2, 1999.
  • Send reprint requests to: Dr. Dimitrios L. Kalpaxis, Laboratory of Biochemistry, School of Medicine, University of Patras, GR-26500 Patras, Greece. E-mail: Dimkal{at}med.upatras.gr

  • Dedicated to the memory of Professor C. Coutsogeorgopoulos, who established research on protein synthesis in our laboratory.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Slow Sequential Conformational Changes in Escherichia coli Ribosomes Induced by Lincomycin: Kinetic Evidence

Sofia Kallia-Raftopoulos and Dimitrios L. Kalpaxis
Molecular Pharmacology November 1, 1999, 56 (5) 1042-1046; DOI: https://doi.org/10.1124/mol.56.5.1042

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Research ArticleArticle

Slow Sequential Conformational Changes in Escherichia coli Ribosomes Induced by Lincomycin: Kinetic Evidence

Sofia Kallia-Raftopoulos and Dimitrios L. Kalpaxis
Molecular Pharmacology November 1, 1999, 56 (5) 1042-1046; DOI: https://doi.org/10.1124/mol.56.5.1042
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