7mdz

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80S rabbit ribosome stalled with benzamide-CHX

Structural highlights

7mdz is a 10 chain structure with sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.2Å
Ligands:MG, Z2V, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RL8_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 PubMed

Employed 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.

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See Also

References

  1. ↑ Muhs M, Hilal T, Mielke T, Skabkin MA, Sanbonmatsu KY, Pestova TV, Spahn CM. Cryo-EM of Ribosomal 80S Complexes with Termination Factors Reveals the Translocated Cricket Paralysis Virus IRES. Mol Cell. 2015 Feb 5;57(3):422-432. doi: 10.1016/j.molcel.2014.12.016. Epub 2015 , Jan 15. PMID:25601755 doi:http://dx.doi.org/10.1016/j.molcel.2014.12.016
  2. ↑ Brown A, Shao S, Murray J, Hegde RS, Ramakrishnan V. Structural basis for stop codon recognition in eukaryotes. Nature. 2015 Aug 27;524(7566):493-6. doi: 10.1038/nature14896. Epub 2015 Aug 5. PMID:26245381 doi:http://dx.doi.org/10.1038/nature14896
  3. ↑ Shao S, Murray J, Brown A, Taunton J, Ramakrishnan V, Hegde RS. Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes. Cell. 2016 Nov 17;167(5):1229-1240.e15. doi: 10.1016/j.cell.2016.10.046. PMID:27863242 doi:http://dx.doi.org/10.1016/j.cell.2016.10.046
  4. ↑ Flis J, Holm M, Rundlet EJ, Loerke J, Hilal T, Dabrowski M, Burger J, Mielke T, Blanchard SC, Spahn CMT, Budkevich TV. tRNA Translocation by the Eukaryotic 80S Ribosome and the Impact of GTP Hydrolysis. Cell Rep. 2018 Dec 4;25(10):2676-2688.e7. doi: 10.1016/j.celrep.2018.11.040. PMID:30517857 doi:http://dx.doi.org/10.1016/j.celrep.2018.11.040
  5. ↑ Koga Y, Hoang EM, Park Y, Keszei AFA, Murray J, Shao S, Liau BB. Discovery of C13-Aminobenzoyl Cycloheximide Derivatives that Potently Inhibit Translation Elongation. J Am Chem Soc. 2021 Sep 1;143(34):13473-13477. PMID:34403584 doi:10.1021/jacs.1c05146

Contents


PDB ID 7mdz

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OCA

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