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Structural Insight into Interaction between C20 Phenylalanyl Derivative of Tylosin and Ribosomal Tunnel

G. I. Makarov1,2, N. V. Sumbatyan2, and A. A. Bogdanov1,3*

1Lomonosov Moscow State University, Faculty of Chemistry, 119991 Moscow, Russia

2South Ural State University, 454080 Chelyabinsk, Russia

3Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia; E-mail: bogdanov@belozersky.msu.ru

* To whom correspondence should be addressed.

Received April 21, 2017; Revision received May 10, 2017
Macrolides are clinically important antibiotics that inhibit protein biosynthesis on ribosomes by binding to ribosomal tunnel. Tylosin belongs to the group of 16-membered macrolides. It is a potent inhibitor of translation whose activity is largely due to reversible covalent binding of its aldehyde group with the base of A2062 in 23S ribosomal RNA. It is known that the conversion of the aldehyde group of tylosin to methyl or carbinol groups dramatically reduces its inhibitory activity. However, earlier we obtained several derivatives of tylosin having comparable activity in spite of the fact that the aldehyde group of tylosin in these compounds was substituted with an amino acid or a peptide residue. Details of the interaction of these compounds with the ribosome that underlies their high inhibitory activity were not known. In the present work, the structure of the complex of tylosin derivative containing in position 20 the residue of ethyl ester of 2-imino(oxy)acetylphenylalanine with the tunnel of the E. coli ribosome was identified by means of molecular dynamics simulations, which could explain high biological activity of this compound.
KEY WORDS: ribosome, simulation, antibiotics, tylosin, molecular dynamics

DOI: 10.1134/S0006297917080077