The ribosome is a molecular machine responsible for protein synthesis and a major target for small-molecule inhibitors. Compared to the wealth of structural information available on ribosome-targeting antibiotics in bacteria, our understanding of the binding mode of ribosome inhibitors in eukaryotes is currently limited. Here we used X-ray crystallography to determine 16 high-resolution structures of 80S ribosomes from Saccharomyces cerevisiae in complexes with 12 eukaryote-specific and 4 broad-spectrum inhibitors. All inhibitors were found associated with messenger RNA and transfer RNA binding sites. In combination with kinetic experiments, the structures suggest a model for the action of cycloheximide and lactimidomycin, which explains why lactimidomycin, the larger compound, specifically targets the first elongation cycle. The study defines common principles of targeting and resistance, provides insights into translation inhibitor mode of action and reveals the structural determinants responsible for species selectivity which could guide future drug development.
Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Global Symmetry: Asymmetric - C1 Global Stoichiometry: Hetero 79-mer - AA2AB1AC1AD1AE1AF1AG1AH1AI1AJ1AK1AL1AM1AN1AO1AP1AQ1AR1AS1AT1AU1AV1AW1AX1AY1AZ1Aa1Ab1Ac1Ad1Ae1Af1Ag1Ah1Ai1Aj1Ak1Al1Am1An1Ao1Ap1Aq1Ar1As1At1Au1Av1Aw1Ax1Ay1Az1BA1BB1BC1BD1BE1BF1BG1BH1BI1BJ1BK1BL1BM1BN1BO1BP1BQ1BR1BS1BT1BU1BV1BW1BX1BY1BZ1 Local Symmetry: Cyclic - C2 (Explore in 3D) Local Stoichiometry: Homo 2-mer - AA2
Local Symmetry: Cyclic - C2 (Explore in 3D) Local Stoichiometry: Homo 2-mer - AA2