E-site drug specificity of the human pathogen Candida albicans ribosome

Yury Zgadzay (1, 2) , Olga Kolosova (1) , Artem Stetsenko (3) , Cheng Wu (4) , David Bruchlen (1) , Konstantin Usachev (2, 5) , Shamil Validov (2, 5) , Lasse Jenner (1) , Andrey Rogachev (6, 7) , Gulnara Yusupova (1) , Matthew Sachs (4) , Albert Guskov (6, 3) , Marat Yusupov (1, 2, 5)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 KFU - Kazan Federal University
3 University of Groningen [Groningen]
4 Texas A&M University [College Station]
5 Kazan Scientific Centre of the Russian Academy of Sciences
6 MIPT - Moscow Institute of Physics and Technology [Moscow]
7 JINR - Joint Institute for Nuclear Research

Candida albicans 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 C. albicans 80 S 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 C. albicans and forms a basis for further antifungal drug development.

Domaines: Mycologie; Biologie structurale [q-bio.BM]

Yury Zgadzay, Olga Kolosova, Artem Stetsenko, Cheng Wu, David Bruchlen, et al.. E-site drug specificity of the human pathogen Candida albicans ribosome. Science Advances , 2022, 8 (21), pp.eabn1062. ⟨10.1126/sciadv.abn1062⟩. ⟨hal-03813407⟩