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TitleStructural Basis for Linezolid Binding Site Rearrangement in the Ribosome.
Journal, issue, pagesmBio, Vol. 8, Issue 3, Year 2017
Publish dateMay 9, 2017
AuthorsMatthew J Belousoff / Zohar Eyal / Mazdak Radjainia / Tofayel Ahmed / Rebecca S Bamert / Donna Matzov / Anat Bashan / Ella Zimmerman / Satabdi Mishra / David Cameron / Hans Elmlund / Anton Y Peleg / Shashi Bhushan / Trevor Lithgow / Ada Yonath /
PubMed AbstractAn unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of This high-resolution ...An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site. The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821-832, 2015, https://doi.org/10.1038/nrd4675). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance.
External linksmBio / PubMed:28487427 / PubMed Central
MethodsEM (single particle)
Resolution3.6 - 3.9 Å
Structure data

EMDB-8369, PDB-5t7v:
Methicillin Resistant, Linezolid resistant Staphylococcus aureus 70S ribosome (delta S145 uL3)
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-8402, PDB-5tcu:
Methicillin sensitive Staphylococcus aureus 70S ribosome
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-PAR:
PAROMOMYCIN / Antimicrobial, medication*YM

Source
  • staphylococcus aureus (bacteria)
  • staphylococcus aureus (strain nctc 8325) (bacteria)
  • staphylococcus aureus subsp. aureus nctc 8325 (bacteria)
KeywordsRIBOSOME / 70S ribosome / methicillin resistant / linezolid resistant / cryoEM / ribosome/antibiotic / Staphylococcus aureus / ribosome-antibiotic complex

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