7mdz
80S rabbit ribosome stalled with benzamide-CHX
Structural highlights
FunctionRL8_RABIT Component of the large ribosomal subunit (PubMed:25601755, PubMed:26245381, PubMed:27863242, PubMed:30517857). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:25601755, PubMed:26245381, PubMed:27863242, PubMed:30517857).[1] [2] [3] [4] Publication Abstract from PubMedEmployed for over half a century to study protein synthesis, cycloheximide (CHX, 1) is a small molecule natural product that reversibly inhibits translation elongation. More recently, CHX has been applied to ribosome profiling, a method for mapping ribosome positions on mRNA genome-wide. Despite CHX's extensive use, CHX treatment often results in incomplete translation inhibition due to its rapid reversibility, prompting the need for improved reagents. Here, we report the concise synthesis of C13-amide-functionalized CHX derivatives with increased potencies toward protein synthesis inhibition. Cryogenic electron microscopy (cryo-EM) revealed that C13-aminobenzoyl CHX (8) occupies the same site as CHX, competing with the 3' end of E-site tRNA. We demonstrate that 8 is superior to CHX for ribosome profiling experiments, enabling more effective capture of ribosome conformations through sustained stabilization of polysomes. Our studies identify powerful chemical reagents to study protein synthesis and reveal the molecular basis of their enhanced potency. Discovery of C13-Aminobenzoyl Cycloheximide Derivatives that Potently Inhibit Translation Elongation.,Koga Y, Hoang EM, Park Y, Keszei AFA, Murray J, Shao S, Liau BB J Am Chem Soc. 2021 Sep 1;143(34):13473-13477. doi: 10.1021/jacs.1c05146. Epub , 2021 Aug 17. PMID:34403584[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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