Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size

Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size

Macrolide antibiotic binding to the ribosome inhibits catalysis of peptide bond formation between specific donor and acceptor substrates. Why particular reactions are problematic for the macrolide-bound ribosome remains unclear. Using comprehensive mutational analysis and biochemical experiments wit...

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Main Authors: Shanmugapriya Sothiselvam, Sandro Neuner, Lukas Rigger, Dorota Klepacki, Ronald Micura, Nora Vázquez-Laslop, Alexander S. Mankin
Format: Article
Language:English
Published: Elsevier 2016-08-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124716309044
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spelling doaj-5de8ece61be24c608cf1c9d5672577a12020-11-25T01:46:35ZengElsevierCell Reports2211-12472016-08-011671789179910.1016/j.celrep.2016.07.018Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and SizeShanmugapriya Sothiselvam0Sandro Neuner1Lukas Rigger2Dorota Klepacki3Ronald Micura4Nora Vázquez-Laslop5Alexander S. Mankin6Center for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USAInstitute of Organic Chemistry and Center for Molecular Biosciences, Leopold Franzens University, 6020 Innsbruck, AustriaInstitute of Organic Chemistry and Center for Molecular Biosciences, Leopold Franzens University, 6020 Innsbruck, AustriaCenter for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USAInstitute of Organic Chemistry and Center for Molecular Biosciences, Leopold Franzens University, 6020 Innsbruck, AustriaCenter for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USACenter for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USAMacrolide antibiotic binding to the ribosome inhibits catalysis of peptide bond formation between specific donor and acceptor substrates. Why particular reactions are problematic for the macrolide-bound ribosome remains unclear. Using comprehensive mutational analysis and biochemical experiments with synthetic substrate analogs, we find that the positive charge of these specific residues and the length of their side chains underlie inefficient peptide bond formation in the macrolide-bound ribosome. Even in the absence of antibiotic, peptide bond formation between these particular donors and acceptors is rather inefficient, suggesting that macrolides magnify a problem present for intrinsically difficult substrates. Our findings emphasize the existence of functional interactions between the nascent protein and the catalytic site of the ribosomal peptidyl transferase center.http://www.sciencedirect.com/science/article/pii/S2211124716309044
collection DOAJ
language English
format Article
sources DOAJ
author Shanmugapriya Sothiselvam
Sandro Neuner
Lukas Rigger
Dorota Klepacki
Ronald Micura
Nora Vázquez-Laslop
Alexander S. Mankin
spellingShingle Shanmugapriya Sothiselvam
Sandro Neuner
Lukas Rigger
Dorota Klepacki
Ronald Micura
Nora Vázquez-Laslop
Alexander S. Mankin
Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size
Cell Reports
author_facet Shanmugapriya Sothiselvam
Sandro Neuner
Lukas Rigger
Dorota Klepacki
Ronald Micura
Nora Vázquez-Laslop
Alexander S. Mankin
author_sort Shanmugapriya Sothiselvam
title Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size
title_short Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size
title_full Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size
title_fullStr Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size
title_full_unstemmed Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size
title_sort binding of macrolide antibiotics leads to ribosomal selection against specific substrates based on their charge and size
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2016-08-01
description Macrolide antibiotic binding to the ribosome inhibits catalysis of peptide bond formation between specific donor and acceptor substrates. Why particular reactions are problematic for the macrolide-bound ribosome remains unclear. Using comprehensive mutational analysis and biochemical experiments with synthetic substrate analogs, we find that the positive charge of these specific residues and the length of their side chains underlie inefficient peptide bond formation in the macrolide-bound ribosome. Even in the absence of antibiotic, peptide bond formation between these particular donors and acceptors is rather inefficient, suggesting that macrolides magnify a problem present for intrinsically difficult substrates. Our findings emphasize the existence of functional interactions between the nascent protein and the catalytic site of the ribosomal peptidyl transferase center.
url http://www.sciencedirect.com/science/article/pii/S2211124716309044
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