Механизмы клеточной устойчивости к ингибитору трансляции микроцину С и родственным соединениям

Выводы.

1) MccF является сериновой пептидазой, которая обеспечивает устойчивость клетки к МсС за счет гидролиза амидной связи между пептидной и нуклеотидной частями антибиотика. Кроме МсС MccF гидролизует aaSA с полярными отрицательно заряженными аминоацильными группами.

2) Определена структура MccF и выяснена молекулярная природа узнавания субстрата. Специфичность MccF к аденилированным субстратам опосредована остатком ароматической аминокислоты, расположенном в петле между двумя доменами белка.

3) В S66 семействе пептидаз найдена группа гомологов MccF, которые содержат междоменную петлю с консервативным ароматическим остатком. Показано, что некоторые представители этой группы гидролизуют МсС и aaSA. Гомолог MccF из В. anthracis обладает сходной с MccF из Е. coli структурой и механизмом действия и в физиологических условиях защищает клетки от химического аналога МсС.

Публикации в журналах:

Tikhonov A, Kazakov Т, Semenova Е, Serebryakova М, Vondenhoff G, Van Aerschot A, Reader JS, Govorun VM, Severinov K. The mechanism of Microcin С resistance provided by the MccF peptidase. Journal of Biological Chemistry. 2010 Dec 3- 285(49): 37 944−52.

Agarwal V, Tikhonov A, Metlytskaya A, Severinov K, and Nair S. Structure and function of a serine carboxypeptidase adapted for degradation of the protein synthesis antibiotic microcin CI. Proceedings of the National Academy of Sciences USA. 2012 Mar 20- 109(12): 4425−30.

Nocek BTikhonov ABabnigg GMinyi GuZhou MMakarova KSVondenhoff GAerschot AVKwon KAnderson WFSeverinov KJoachimiak A. Structural and functional characterization of microcin С resistance peptidase MccF from Bacillus anthracis. Journal of Molecular Biology. 2012 Jul 20- 420(4−5): 366−83.

Заключение

.

В данной работе с помощью разнообразных методов был подробно изучен механизм действия МссР, за счет которого клетки приобретают устойчивость к МсС. Полученные нами результаты расширяют представления о спектре субстратной специфичности и биохимии сериновых пептидаз. Кроме того, мы обнаружили большое количество гомологов МссР среди бактерий, и показали, что некоторые из найденных гомологов способны гидролизовать субстраты МссР. Эти результаты косвенно указывают на значительное распространение токсичных негидролизуемых аминоацил-аденилатов в бактериальных сообществах. Изучение физиологических функций найденных белков представляется интересной научной задачей. !!" «!!» .

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