Visualizing host-virus interactions at high resolutions in situ

TL;DR

This paper presents new cryo-EM techniques to visualize virus-cell interactions and protein synthesis at high resolution in their natural environments.

Contribution

The study introduces an advanced in situ cryo-EM method combining automated FIB milling to achieve unprecedented structural detail in native biological contexts.

Findings

A 2.19 Å resolution structure of the human 80S ribosome was resolved using the new method.

23 distinct functional states of the ribosome were uncovered.

High-resolution insights were obtained from cells treated with homoharringtonine and cycloheximide.

Abstract

Understanding virus and macromolecular structures in their natural viral and cellular environments is key to advancing biology and improving health. Here, I highlight recent advancements in in situ single-particle cryo-electron microscopy (cryo-EM), which has enabled us to observe how HIV-1 capsids interact with antiviral compounds directly within the virus’s native environment. Additionally, we showcase the unprecedented detail of protein synthesis in human cells using a method that combines automated cryo-focused ion beam (FIB) milling with in situ single-particle cryo-EM. With this approach, we resolved a 2.19 Å resolution structure of the human 80S ribosome and uncovered 23 distinct functional states. We also obtained high-resolution structural insights from cells treated with the anti-tumor drug homoharringtonine and the inhibitor cycloheximide. Collectively, our work represents a significant advancement in structural studies within natural contexts, highlighting a powerful tool to investigate virus infection and basic biology.