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

Journal:Nature Structural&molecular biology

Key Words:The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyltransfer RNA 3!-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest.

Summary:The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number
of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846
binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the
nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyltransfer
RNA 3!-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA
libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation,
depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation
by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins
of therapeutic interest.

First Author:Wenfei Li*

Correspondence Author:J. Cate#

All the Authors:Ward, K. McClure, S. Chang, E. Montabana, S. Liras, R. Dullea

Volume:26

Issue:6

Page Number:501-509

Translation or Not:No

Date of Publication:2019-06

Links to Published Journals:https://www.nature.com/articles/s41594-019-0236-8

Release Time:2021-05-24