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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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An interesting example of the dynamic behavior of ribosome nascent peptide exit tunnel (NPET) is its interaction with antibiotics, such as chloramphenicol (CLM) and linezolid (LZD). Modern conceptions about the mechanism of their action are based on Xray diffraction analysis and claim that these antibiotics bound to the A-site of the peptidyl transferase center prevent binding of aminoacyl-tRNA. But biochemical experiments revealed that these antibiotics does not exclude peptidyl transferase reaction and selectively inhibits synthesis of certain peptide sequences (Marks et al., 2016), which contradicts accepted mechanism. Our simulation of CLM interaction with the E. coli ribosome in A,Pstate suggests that CLM forms stacking interactions with U2506 and Ψ2504 bases, embedding itself between them, and hydrogen bonds with G2061 and Ψ2504 bases, while the dichloroacetyl moiety of CLM is oriented into NPET lumen, which favors its interaction with the nascent peptide. We obtained similar results for LZD: its morpholine moiety is embedded between U2506 and Ψ2504 bases, and its oxazolidinone ring forms hydrogen bonds with the G2061 base, being able to interact with the nascent peptide. CLM and LZD complexes structures modeled by us are in good agreement with the known biochemical data, allowing to explain selective inhibition of peptide synthesis. Noteworthy, U2506 and Ψ2504 nucleotides accept the conformation necessary for this interaction only during the translation elongation. Thus, the dynamic appearance of a binding site that exists only in a certain functional state is possible in the ribosome. This confirms the Koshland’s principle of induced fit, according to which the ligand and the constitutively existing binding site mutually adjust their conformations in the process of interaction. All the calculations were performed with the Lomonosov supercomputer of Moscow State University using GROMACS 5 and PLUMED 2 packages and parm99sb force field.