2026/05/06 – Joey Davis

Structural Ensembles as Molecular Phenotypes of Translation

Structural studies of ribosomes by single particle cryogenic electron microscopy (cryoEM) have traditionally relied on purified or reconstituted samples, with particles often trapped in desired states using genetic, pharmacological, or biochemical perturbations. While informative, such approaches can fail to capture the full diversity of structural states and associated factors present in cells. In this talk, I will describe our development of cryoDRGN and cryoPRISM, a rapid ex vivo workflow for high-resolution analysis of ribosomes directly from cell lysates, and show how this approach enables visualization and quantitative analysis of ribosomal ensembles spanning assembly, translation, and hibernation under near-native conditions. I will focus on the idea that these structural ensembles can be interpreted as molecular phenotypes, and that perturbations such as small molecules, protein factors, or environmental stresses reshape the structural landscape by shifting the distribution of states. Importantly, I will discuss how such molecular phenotypes can reveal the mechanisms by which these perturbations modulate translation. Examples will be drawn from our recent work in bacterial and archaeal systems, illustrating how we are using cryoPRISM to understand how translation is modulated across diverse biological contexts.