Cryo-EM in drug discovery: achievements, limitations and prospects

Abstract

Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug discovery has been heavily limited by two issues: the minimum size of the structures it can be used to study and the resolution of the images. However, recent technological advances - including the development of direct electron detectors and more effective computational image analysis techniques - are revolutionizing the utility of cryo-EM, leading to a burst of high-resolution structures of large macromolecular assemblies. These advances have raised hopes that single-particle cryo-EM might soon become an important tool for drug discovery, particularly if they could enable structural determination for 'intractable' targets that are still not accessible to X-ray crystallographic analysis. This article describes the recent advances in the field and critically assesses their relevance for drug discovery as well as discussing at what stages of the drug discovery pipeline cryo-EM can be useful today and what to expect in the near future.

General and robust covalently linked graphene oxide affinity grids for high-resolution cryo-EM

“…solutions through blotting, the grid is plunged into liquid ethane and the biological samples are vitrified in amorphous ice 3 . Proteins of interest are thus preserved in hydrated state 4 .…”

Elucidating Tau function and dysfunction in the era of cryo-EM

“…If single-particle cryo-EM has taken the general field of structural biology by storm (1,2), in its application to the subfield of neuronal physiology and pathology, it should rather be considered a tsunami. The atomic structures of the ␥-secretase complex, first by itself (3,4) and more recently in complex with a fragment of the amyloid precursor protein (5) or with Notch (6), have highlighted the mechanisms of the complex machinery that produces the amyloid-␤ peptide, one of the molecular hallmarks of Alzheimer's disease (AD).…”

The role of small-angle scattering in structure-based screening applications

“…The recent advent and increasing feasibility of cryo-EM maps at near-atomic and atomic resolutions have inspired discussions on their potential drug discovery applications (Merk et al, 2016;Renaud et al, 2018). The breakthroughs in both resolution required for direct atomic placement (< 3Å) and minimum resolvable particle sizes are regarded as key advances for the technique to become viable as a means to directly visualise bound complexes, particularly for systems that are not known to crystallise.…”