Bitesize Bio

Cryo-EM reveals ligand binding in the SARS-CoV-2 spike protein and the human CDK-activating kinase

January 30, 2023
In this webinar, you will learn:

The importance of high resolution and visualization for small ligands when using cryo-EM to investigate human disease
The challenges involved in determining the cryo-EM structure of human CDK-activating kinase bound to nucleotide analogues and inhibitors
How a druggable free fatty acid binding pocket was discovered in the SARS-CoV-2 spike glycoprotein
How linoleic acid can bind to this pocket and how this affects the conformation of the SARS-CoV-2 spike glycoprotein.
In the last few years, cryo-electron microscopy has revolutionized structural biology by enabling high-resolution visualization of biomolecular complexes refractory to analysis using other techniques. The highest resolutions achieved have been for large or symmetric molecular complexes. However, many targets that are highly relevant for human health, including for drug design efforts, are neither particularly large, nor highly symmetric, or may exhibit intrinsic flexibility that complicates structure determination efforts. It is, therefore, critical when harnessing the power of cryo-EM to fight human disease that such targets are resolved to a high resolution, and bound small-molecule ligands visualized.

Dr. Greber and colleagues have determined the cryo-EM structure of the human CDK-activating kinase, a small asymmetric complex that is a cancer drug target, bound to nucleotide analogues and inhibitors, at up to 2.5 Å resolution (Figure 1). The first part of the webinar will describe these efforts and the challenges involved.

Prof Christiane Schaffitzel and colleagues discovered a druggable free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike glycoprotein (Figure 2). The structure at 2.85 Å resolution revealed a tube-shaped density bound to the pocket, which, as shown by mass spectroscopy, corresponds to linoleic acid (LA), an essential fatty acid. The binding of LA locks spike protein in a compact conformation which is not compatible with ACE2 receptor binding and infection.


1. Toelzer, C. et al. Free fatty acid binding pocket in the locked structure of SARS CoV-2 spike protein. Science. (2020). doi: 10.1126/science.abd3255

2. Greber, BJ. et al. The cryoelectron microscopy structure of the human CDK-activating kinase. PNAS. 117(37) 22849-57; (2020). doi: 10.1073/pnas.2009627117