Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders

Alena Kroupova, Valentina A. Spiteri, Zoe J. Rutter, Hirotake Furihata, Darren Darren, Sarath Ramachandran, Sohini Chakraborti, Kevin Haubrich, Julie Pethe, Denzel Gonzales, Andre J. Wijaya, Maria Rodriguez-Rios, Manon Sturbaut, Dylan M. Lynch, William Farnaby, Mark A. Nakasone, David Zollman () and Alessio Ciulli ()
Additional contact information
Alena Kroupova: University of Dundee
Valentina A. Spiteri: University of Dundee
Zoe J. Rutter: University of Dundee
Hirotake Furihata: University of Dundee
Darren Darren: University of Dundee
Sarath Ramachandran: University of Dundee
Sohini Chakraborti: University of Dundee
Kevin Haubrich: University of Dundee
Julie Pethe: University of Dundee
Denzel Gonzales: University of Dundee
Andre J. Wijaya: University of Dundee
Maria Rodriguez-Rios: University of Dundee
Manon Sturbaut: University of Dundee
Dylan M. Lynch: University of Dundee
William Farnaby: University of Dundee
Mark A. Nakasone: University of Dundee
David Zollman: University of Dundee
Alessio Ciulli: University of Dundee

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The ubiquitin E3 ligase cereblon (CRBN) is the target of therapeutic drugs thalidomide and lenalidomide and is recruited by most targeted protein degraders (PROTACs and molecular glues) in clinical development. Biophysical and structural investigation of CRBN has been limited by current constructs that either require co-expression with the adaptor DDB1 or inadequately represent full-length protein, with high-resolution structures of degrader ternary complexes remaining rare. We present the design of CRBNmidi, a construct that readily expresses from E. coli with high yields as soluble, stable protein without DDB1. We benchmark CRBNmidi for wild-type functionality through a suite of biophysical techniques and solve high-resolution co-crystal structures of its binary and ternary complexes with degraders. We qualify CRBNmidi as an enabling tool to accelerate structure-based discovery of the next generation of CRBN based therapeutics.

Date: 2024
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DOI: 10.1038/s41467-024-52871-9

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