Naslov
A new insight into mupirocin resistance of bacterial isoleucyl-tRNA synthetases

Autori
Brkić, Alojzije ; Leibundgut, Marc ; Ban, Nenad ; Gruić-Sovulj, Ita

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
5th Mini Symposium of Section of Medicinal and Pharmaceutical Chemistry / Maja Beus, Đani Škalamera - Zagreb : Hrvatsko kemijsko društvo, Sekcija za medicinsku i farmaceutsku kemiju, 2021, 10-10

Skup
5th Mini Symposium of Section of Medicinal and Pharmaceutical Chemistry

Mjesto i datum
Zagreb, Hrvatska, 30.11.2021

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
isoleucyl-tRNA-synthetase ; mupirocin ; structure ; IleRS1 ; IleRS2
(isoleucyl-tRNA-synthetase ; C-terminal domain ; structure ; IleRS1 ; IleRS2)

Sažetak
Ribosomal protein biosynthesis is a key cellular process because proteins are the main cellular building blocks on all scales of life. Ensuring substrates for protein biosynthesis, evolutionarily conserved aminoacyl-tRNA synthetases (aaRSs) covalently couple amino acids to cognate tRNAs. This makes aaRSs important targets for natural and man-made antibiotics. A good example are isoleucyl-tRNA-synthetases (IleRS) which are susceptible to inhibition with mupirocin, a naturally produced antibiotic from the bacterium Pseudomonas fluorescens. Bacterial IleRSs cluster into two clades differing in susceptibility to mupirocin inhibition. IleRS1, present in most pathogenic bacteria, are up to 9 orders of magnitude more susceptible to mupirocin inhibition than bacterial IleRS2, which share similarities with eucaryotic IleRS, thus making IleRS1 favorable pharmaceutical targets. To investigate the origin of mupirocin insensitivity in IleRS2, crystal structures of IleRS2, and IleRS1 in a complex with mupirocin and a nonhydrolyzable analog of the reaction intermediate, Ile-AMS, were solved. Bacillus megaterium was chosen because it has genomic copies of both IleRS1 and IleRS2. By analyzing the solved structures we have shown that mupirocin binding to the two IleRS types, although similar, differs in the number of established mupirocin interactions and steric rearrangements which coincide with mupirocin binding. In IleRS2, mupirocin lacks two active site interactions compared to IleRS1 and the binding coincides with steric rearrangements of key active site parts. In contrast, the IleRS1 active site seems preformed for high-affinity mupirocin binding, with only a little steric rearrangement taking place upon the mupirocin binding. Thus, we propose a mechanism wherein the differences between mupirocin resistance of IleRS1 and IleRS2 are not only correlated to the differences in the interactions mupirocin establishes in the active site, but also to the steric rearrangements (or lack thereof) of the IleRS active site that accompany mupirocin binding.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Interdisciplinarne prirodne znanosti

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