Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule

Small molecules that target the ribosome generally have a global impact on protein synthesis. However, the drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small subset of proteins by an unknown mechanism. In high-resolution cryo-electron microscopy (cryo-EM) structures of human ribosome nascent chain complexes stalled by PF846, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by the 28S ribosomal RNA (rRNA), and redirects the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state, with peptidyl-tRNA occupying a mixture of A/A and hybrid A/P sites. These results provide a structural foundation for a new strategy for developing small molecules that selectively inhibit the production of proteins of therapeutic interest.