@article {8832,
	title = {Cryo-EM structures reveal the molecular mechanism of HflX-mediated erythromycin resistance in mycobacteria [National Cryo-EM Facility, BLiSC]},
	journal = {Structure},
	year = {2024},
	month = {2024 Jul 08},
	abstract = {<p>Mycobacterial HflX confers resistance against macrolide antibiotics. However, the exact molecular mechanism is poorly understood. To gain further insights, we determined the cryo-EM structures of M.\&nbsp;smegmatis (Msm) HflX-50S subunit and 50S subunit-erythromycin (ERY) complexes at a global resolution of approximately 3\&nbsp;{\r A}. A conserved nucleotide A2286 at the gate of nascent peptide exit tunnel (NPET) adopts a swayed conformation in HflX-50S complex and interacts with a loop within the linker helical (LH) domain of MsmHflX that contains an additional 9 residues insertion. Interestingly, the swaying of this nucleotide, which is usually found in the non-swayed conformation, is induced by erythromycin binding. Furthermore, we observed that erythromycin decreases HflX{\textquoteright}s ribosome-dependent GTP hydrolysis, resulting in its enhanced binding and anti-association activity on the 50S subunit. Our findings reveal how mycobacterial HflX senses the presence of macrolides at the peptide tunnel entrance and confers antibiotic resistance in mycobacteria.</p>
},
	issn = {1878-4186},
	doi = {10.1016/j.str.2024.06.016},
	author = {Srinivasan, Krishnamoorthi and Banerjee, Aneek and Sengupta, Jayati}
}
