Explore Mutational Landscape
Cyrus’s protein biochemistry capabilities include advanced selection methodologies in both yeast and mammalian cell systems. These tools can interrogate large numbers of mutations in cell surface receptors and many globular proteins, offering a unique path forward for protein optimization based on high quality, physiologically-relevant data in eukaryotic or – specifically – human cells.
Exhaustive single point mutations of ACE2 were tested by yeast display to identify mutations that affect binding to SARS-CoV-2’s Spike protein. By sequencing the mutations that retained binding, we can explore sequence diversity. Deep mutational scans identified conserved positions (in blue) that are critical for binding. Positions with high mutation tolerance (in yellow) are under selection to change. From “Narayanan KK, Procko E. Deep Mutational Scanning of Viral Glycoproteins and Their Host Receptors. Front Mol Biosci. 2021 Apr 9;8:636660.”
Eric Procko – Director of Discovery at Cyrus
Mutational Scanning
Erik Procko’s lab, first at UIUC and now at Cyrus, has developed ‘Big Data’ tools for deep mutational scanning of a variety of proteins in mammalian cells. By combining in vitro evolution with deep sequencing, it becomes possible to characterize the phenotypes of thousands of receptor mutants in a single experiment, and a comprehensive sequence-fitness landscape of a protein can be experimentally determined. Mutations can then be identified that alter protein activity, with a particular focus on finding mutations that optimize desirable drug-like properties. These methods can also be used to understand conformational equilibria in complex proteins with large conformational changes, making certain categories of protein amenable to biophysical understanding and optimization for drug discovery in ways that were not possible with current biophysical techniques
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