Cryo-EM Reveals Ligand Binding in the SARS-CoV-2 Spike Protein and the Human CDK-activating Kinase
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Christiane Schaffitzel
Christiane Schaffitzel studied biochemistry at Leibniz University and Medical School (MHH) in Hannover (Germany) and at ETH Zürich (Switzerland). After her PhD thesis at the University of Zürich and a Postdoc at the ETH Zürich, she became Oberassistant/ Lecturer and was awarded a Habilitation in Biochemistry from ETH in 2008. In 2007, she was appointed team leader at the European Molecular Biology Laboratory in Grenoble, France. Since 2014, Christiane is a Professor of Biochemistry at the University of Bristol. She established high-resolution electron cryo-microscopy in Bristol and leads the GW4 cryo-EM facility since 2017. Christiane’s research is centred around the ribosome and protein synthesis. Her team studies translation using biochemistry and cryo-EM. Her research on translational control was funded by the European Research Council (ERC Starting Grant)and now is supported by a Wellome Trust Investigator award. During the lockdown, Christiane and colleagues started working of the cryo-EM structure of SRS-CoV-2 Spike protein leading to the discovery of a druggable pocket in the Spike protein which binds the essential free fatty acid linoleic acid.
CloseDr. Basil Greber
Dr.Basil Greber obtained his undergraduate degrees in Biology from ETH Zurich, Switzerland. After a 6-month stay in the laboratory of Prof. Manuel Mendoza at the Centre for Genomic Regulation in Barcelona, Basil returned to Zurch to join the laboratory of Prof. Nenad Ban for his doctoral thesis work. During Basils time in Zurich, the development of high-resolution cryo-electron microscopy transformed structural biology. Application of these new technologies to mitochondrial ribosomes and ribosome assembly complexes led to some of the earliest high-resolution cryo-EM structures and several unexpected discoveries. Basil was awarded the Scaringe Award of the RNA Society for these studies.
In 2015, Basil moved to the laboratory of Prof. Eva Nogales at the University of California, Berkeley as a postdoctoral fellow, supported by the Swiss National Science Foundation. There, he determined the complete structure of the human transcription factor TFIIH, a multifunctional protein complex that is critical both for transcription initiation and DNA repair throughout eukaryotes.
Dr. Greber recently joined the Institute of Cancer Research in London as an ICR Fellow to perform structural and functional studies of DNA repair.
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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.
References:
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
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