title: Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size.
abstract: 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.
authors: Center for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USA.
authors: Shanmugapriya
authors: S
authors: Sothiselvam
authors: Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold Franzens University, 6020 Innsbruck, Austria.
authors: Sandro
authors: S
authors: Neuner
authors: Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold Franzens University, 6020 Innsbruck, Austria.
authors: Lukas
authors: L
authors: Rigger
authors: Center for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USA.
authors: Dorota
authors: D
authors: Klepacki
authors: Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold Franzens University, 6020 Innsbruck, Austria.
authors: Ronald
authors: R
authors: Micura
authors: Center for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USA. Electronic address: nvazquez@uic.edu.
authors: Nora
authors: N
authors: Vázquez-Laslop
authors: Center for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, USA. Electronic address: shura@uic.edu.
authors: Alexander S
authors: AS
authors: Mankin
mesh_terms: D020816:Amino Acid Motifs; D001483:Base Sequence; D001665:Binding Sites; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D010458:Peptidyl Transferases / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D018942:Macrolides; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D012346:RNA, Transfer, Amino Acyl; D010458:Peptidyl Transferases