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Chapter 36 : Antibiotics and the Peptidyltransferase Center

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Abstract:

The peptidyltransferase center is the ribosomal site where peptide bond formation occurs and the site where many antibiotics of diverse structures act. By definition, the peptidyltransferase cavity must be able to accommodate any of the diverse hydrophobic and hydrophilic side chains of the amino acids, which suggests that it exhibits a high degree of structural complexity and/or conformational flexibility. An early model for the mechanisms of antibiotic inhibition at the peptidyltransferase center was based on molecular mimicry occurring between the antibiotics and the 3' termini of either aminoacylor peptidyl-tRNAs. Many lines of evidence, including mutational studies and rRNA footprinting and cross-linking studies with antibiotics and tRNAs, strongly suggest that the peptidyltransferase loop of 23S rRNA constitutes the main component of the peptidyltransferase cavity. Some of the cross-linked nucleotides may lie in intermediate states that are occupied while entering or leaving the P' site of the peptidyltransferase center on (otherwise) free ribosomes. Several peptidyltransferase antibiotics, including puromycin, reduced the yield of the sparsomycinribosomal cross-link; the only exceptions were erythromycin and a streptogramin B, both of which belong to the MLS ntibiotics, which do not primarily act on peptide bond formation. Consideration of the synergistic effects observed with streptogramin A and B antibiotics, which potentially represent the two classes of drugs described in this chapter, may yield further insight into their inhibitory mechanisms.

Citation: Porse B, Kirillov S, Garrett R. 2000. Antibiotics and the Peptidyltransferase Center, p 441-450. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch36

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Figures

Image of Figure 1
Figure 1

Secondary structure of the peptidyltransferase loop region (E. coli sequence) showing the sites of drug resistance (solid circles, base changes; solid triangle, lack of modification) and the nucleotides displaying altered chemical reactivities in the presence of drugs (boxed bases). The data are from Moazed and Noller, 1987; Garrett and Rodriguez-Fonseca, 1995; Rodriguez-Fonseca et al., 1995, and references therein; La′zaro et al., 1996; Tan et al., 1996; Porse and Garrett, 1999b; and Leviev et al., 1994.

Citation: Porse B, Kirillov S, Garrett R. 2000. Antibiotics and the Peptidyltransferase Center, p 441-450. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch36
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Image of Figure 2
Figure 2

Structure of sparsomycin.

Citation: Porse B, Kirillov S, Garrett R. 2000. Antibiotics and the Peptidyltransferase Center, p 441-450. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch36
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Image of Figure 3
Figure 3

Structures of a streptogramin A (pristinamycin IIA) (a) and a streptogramin B (pristinamycin IA) (b).

Citation: Porse B, Kirillov S, Garrett R. 2000. Antibiotics and the Peptidyltransferase Center, p 441-450. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch36
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Image of Figure 4
Figure 4

Structure of a putative antibiotic binding motif ( sequence) within the peptidyltransferase center. The newly structured region is shaded, and the alternative base pairing at U2506 with A/G2058 or A2059 is considered in the text. The G occurring at position 2058 in archaeal and eukaryotic rRNAs is shown in italics.

Citation: Porse B, Kirillov S, Garrett R. 2000. Antibiotics and the Peptidyltransferase Center, p 441-450. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch36
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