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Structure paper

TitleStructural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 3577, Year 2021
Publish dateJun 11, 2021
AuthorsCaillan Crowe-McAuliffe / Victoriia Murina / Kathryn Jane Turnbull / Marje Kasari / Merianne Mohamad / Christine Polte / Hiraku Takada / Karolis Vaitkevicius / Jörgen Johansson / Zoya Ignatova / Gemma C Atkinson / Alex J O'Neill / Vasili Hauryliuk / Daniel N Wilson /
PubMed AbstractTarget protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette ...Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaA and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.
External linksNat Commun / PubMed:34117249 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.1 Å
Structure data

EMDB-12331, PDB-7nhk:
LsaA, an antibiotic resistance ABCF, in complex with 70S ribosome from Enterococcus faecalis
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-12332, PDB-7nhl:
VgaA-LC, an antibiotic resistance ABCF, in complex with 70S ribosome from Staphylococcus aureus
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-12333, PDB-7nhm:
70S ribosome from Staphylococcus aureus
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-12334, PDB-7nhn:
VgaL, an antibiotic resistance ABCF, in complex with 70S ribosome from Listeria monocytogenes
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-K:
Unknown entry

ChemComp-PUT:
1,4-DIAMINOBUTANE

ChemComp-FME:
N-FORMYLMETHIONINE

ChemComp-SPD:
SPERMIDINE

Source
  • enterococcus faecalis (bacteria)
  • staphylococcus aureus subsp. aureus nctc 8325 (bacteria)
  • staphylococcus haemolyticus (bacteria)
  • listeria monocytogenes egd-e (bacteria)
KeywordsRIBOSOME / Antibiotic resistance element / ribosomal protein / LsaA / ABCF / target protection / antibiotic resistance / ATPase / protein synthesis / initiation

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