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, 53 (12), 5010-4

Structures of Triacetyloleandomycin and Mycalamide A Bind to the Large Ribosomal Subunit of Haloarcula Marismortui

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Structures of Triacetyloleandomycin and Mycalamide A Bind to the Large Ribosomal Subunit of Haloarcula Marismortui

Güliz Gürel et al. Antimicrob Agents Chemother.

Abstract

Structures have been obtained for the complexes that triacetyloleandomycin and mycalamide A form with the large ribosomal subunit of Haloarcula marismortui. Triacetyloleandomycin binds in the nascent peptide tunnel and inhibits the activity of ribosomes by blocking the growth of the nascent peptide chain. Mycalamide A binds to the E site and inhibits protein synthesis by occupying the space normally occupied by the CCA end of E-site-bound tRNAs.

Figures

FIG. 1.
FIG. 1.
Chemical structures and difference electron density maps. The chemical structures of triacetyloleandomycin and mycalamide A are shown in panels a and c, respectively. The atoms involved in hydrogen bonding interactions with the ribosome are labeled for mycalamide A. The features in the corresponding difference electron density maps that were assigned to triacetyloleandomycin and mycalamide are shown in panels b and d, respectively, with the structures of the drugs superimposed on them. Difference electron density maps are contoured at 3σ.
FIG. 2.
FIG. 2.
Interaction of triacetyloleandomycin with the H. marismortui ribosome compared with other ribosome-macrolide complexes. (a) Comparison of the position and orientation of triacetyloleandomycin (gold) with those of erythromycin (gray) when both are bound to the large ribosomal subunit from H. marismortui (Protein Data Bank accession no. 1YI2) (31). The heteroatoms of triacetyloleandomycin are color coded, with N shown in blue and O in red. Hydrogen bonds are shown as red dashes. (b) The triacetyloleandomycin complex with the H. marismortui ribosome (gold) compared with the triacetyloleandomycin complex with the D. radiodurans ribosome (orange) (Protein Data Bank accession no. 1OND) (4).
FIG. 3.
FIG. 3.
Interaction of mycalamide A with the ribosome. (a) The complex that mycalamide A forms with the H. marismortui ribosome is displayed. Mycalamide A is shown with C in gold, N in blue, and O in red. 23S rRNA residues involved in hydrogen bonding are shown with C in light cyan, N in blue, and O in red. L44e residues involved in drug interactions are shown with C in green, N in blue, and O in red. Hydrogen bonds are shown as red dashes. E. coli base numbering is used for 23S rRNA residues, and H. marismortui numbering is used for L44e protein. (b) Superposition of structures of mycalamide A bound to H. marismortui and the deacylated tRNA mimic CCA oligonucleotide bound to the same ribosome (Protein Data Bank accession no. 1QVG) (25). Mycalamide A is shown with C in gold, N in blue, and O in red. CCA residues are shown in pink. (c) Superposition of the mycalamide A structure with the structure of the complex that 13-deoxytedanolide forms with the H. marismortui ribosome (Protein Data Bank accession no. 2OTJ) (27). Mycalamide A is shown with C in gold, N in blue, and O in red, and 13-deoxytedanolide is shown in green. (d) Superposition of the mycalamide A structure (gold) with the structure of the 70S ribosome from T. thermophilus (Protein Data Bank accession no. 2J03) (28). T. thermophilus protein L28 is shown in green, and T. thermophilus numbers are used for labeling of the protein L28.

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