Visualizing the translation landscape in human cells at high resolution

Wei Zheng, Yuekang Zhang, Jimin Wang, Shuhui Wang, Pengxin Chai, Elizabeth J. Bailey, Chenghao Zhu, Wangbiao Guo, Swapnil C. Devarkar, Shenping Wu, Jianfeng Lin, Kai Zhang, Jun Liu, Ivan B. Lomakin and Yong Xiong ()
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Wei Zheng: Yale University, Department of Molecular Biophysics and Biochemistry
Yuekang Zhang: Yale University, Department of Molecular Biophysics and Biochemistry
Jimin Wang: Yale University, Department of Molecular Biophysics and Biochemistry
Shuhui Wang: Yale University, Department of Molecular Biophysics and Biochemistry
Pengxin Chai: Yale University, Department of Molecular Biophysics and Biochemistry
Elizabeth J. Bailey: Yale University, Department of Molecular Biophysics and Biochemistry
Chenghao Zhu: Yale University, Department of Molecular Biophysics and Biochemistry
Wangbiao Guo: Yale University, Microbial Sciences Institute
Swapnil C. Devarkar: Yale University, Department of Molecular Biophysics and Biochemistry
Shenping Wu: Yale University, Department of Pharmacology
Jianfeng Lin: Yale University, Department of Molecular Biophysics and Biochemistry
Kai Zhang: Yale University, Department of Molecular Biophysics and Biochemistry
Jun Liu: Yale University, Microbial Sciences Institute
Ivan B. Lomakin: Yale University, Department of Dermatology
Yong Xiong: Yale University, Department of Molecular Biophysics and Biochemistry

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Comprehensive in situ structures of macromolecules can transform our understanding of biology and advance human health. Here, we map protein synthesis inside human cells in detail by combining automated cryo-focused ion beam (FIB) milling and in situ single-particle cryo electron microscopy (cryo-EM). With this in situ cryo-EM approach, we resolved a 2.2 Å consensus structure of the human 80S ribosome and unveiled 23 functional states, nearly all better than 3 Å resolution. Compared to in vitro studies, we observed variations in ribosome structures, distinct environments of ion and polyamine binding, and associated proteins such as EDF1 and NACβ that are typically not enriched with purified ribosomes. We also detected additional peptide-related density features on the ribosome and visualized ribosome–ribosome interactions in helical polysomes. Finally, high-resolution structures from cells treated with homoharringtonine and cycloheximide revealed a distinct translational landscape and a spermidine that interacts with cycloheximide at the E site, one of the numerous polyamines that also bind native ribosomes. These results underscore the value of high-resolution in situ studies in the native environment.

Date: 2025
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DOI: 10.1038/s41467-025-65795-9

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