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TitleE-site drug specificity of the human pathogen ribosome.
Journal, issue, pagesSci Adv, Vol. 8, Issue 21, Page eabn1062, Year 2022
Publish dateMay 27, 2022
AuthorsYury Zgadzay / Olga Kolosova / Artem Stetsenko / Cheng Wu / David Bruchlen / Konstantin Usachev / Shamil Validov / Lasse Jenner / Andrey Rogachev / Gulnara Yusupova / Matthew S Sachs / Albert Guskov / Marat Yusupov /
PubMed Abstract is a widespread commensal fungus with substantial pathogenic potential and steadily increasing resistance to current antifungal drugs. It is known to be resistant to cycloheximide (CHX) that binds ... is a widespread commensal fungus with substantial pathogenic potential and steadily increasing resistance to current antifungal drugs. It is known to be resistant to cycloheximide (CHX) that binds to the E-transfer RNA binding site of the ribosome. Because of lack of structural information, it is neither possible to understand the nature of the resistance nor to develop novel inhibitors. To overcome this issue, we determined the structure of the vacant 80 ribosome at 2.3 angstroms and its complexes with bound inhibitors at resolutions better than 2.9 angstroms using cryo-electron microscopy. Our structures reveal how a change in a conserved amino acid in ribosomal protein eL42 explains CHX resistance in and forms a basis for further antifungal drug development.
External linksSci Adv / PubMed:35613268 / PubMed Central
MethodsEM (single particle)
Resolution2.32 - 2.77 Å
Structure data

EMDB-13737: Cryo-EM map of the vacant Candida albicans 80S ribosome
PDB-7pzy: Structure of the vacant Candida albicans 80S ribosome
Method: EM (single particle) / Resolution: 2.32 Å

EMDB-13741, PDB-7q08:
Structure of Candida albicans 80S ribosome in complex with cycloheximide
Method: EM (single particle) / Resolution: 2.56 Å

EMDB-13744: Cryo-EM map of Candida albicans 80S ribosome in complex with phyllanthoside
PDB-7q0f: Structure of Candida albicans 80S ribosome in complex with phyllanthoside
Method: EM (single particle) / Resolution: 2.64 Å

EMDB-13749: Cryo-EM map of the Candida albicans 80S ribosome in complex with anisomycin
PDB-7q0p: Structure of the Candida albicans 80S ribosome in complex with anisomycin
Method: EM (single particle) / Resolution: 2.77 Å

EMDB-13750: Cryo-EM map of the Candida albicans 80S ribosome in complex with blasticidin s
PDB-7q0r: Structure of the Candida albicans 80S ribosome in complex with blasticidin s
Method: EM (single particle) / Resolution: 2.67 Å

Chemicals

ChemComp-SPD:
SPERMIDINE / Spermidine

ChemComp-PUT:
1,4-DIAMINOBUTANE / Putrescine

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-3HE:
4-{(2R)-2-[(1S,3S,5S)-3,5-dimethyl-2-oxocyclohexyl]-2-hydroxyethyl}piperidine-2,6-dione / Cycloheximide

ChemComp-3K5:
3-O-acetyl-2-O-(3-O-acetyl-6-deoxy-beta-D-glucopyranosyl)-6-deoxy-1-O-{[(2R,2'S,3a'R,4''S,5''R,6'S,7a'S)-5''-methyl-4''-{[(2E)-3-phenylprop-2-enoyl]oxy}decahydrodispiro[oxirane-2,3'-[1]benzofuran-2',2''-pyran]-6'-yl]carbonyl}-beta-D-glucopyranose

ChemComp-ANM:
ANISOMYCIN / antibiotic*YM / Anisomycin

ChemComp-BLS:
BLASTICIDIN S / antibiotic*YM / Blasticidin S

Source
  • candida albicans sc5314 (yeast)
  • candida albicans (yeast)
KeywordsRIBOSOME / Candida albicans / cryo-EM / cycloheximide / drug design / phyllanthoside / anisomycin / peptidyl transferase center / blasticidin s

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