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Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders
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Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders
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Journal Article
Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders
2024
Overview
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 CRBN
midi
, a construct that readily expresses from
E. coli
with high yields as soluble, stable protein without DDB1. We benchmark CRBN
midi
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 CRBN
midi
as an enabling tool to accelerate structure-based discovery of the next generation of CRBN based therapeutics.
Structure-based drug discovery of cereblon (CRBN)-recruiting protein degraders has been to date challenging due to limitations with current constructs for recombinant protein expression. In this work, the authors design and validate a truncated CRBN construct, CRBNmidi, that enables crystallization and biophysical characterization of CRBN-binding ligands and degraders.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/103
/ 82/80
/ 82/83
/ Adaptor Proteins, Signal Transducing - chemistry
/ Adaptor Proteins, Signal Transducing - genetics
/ Adaptor Proteins, Signal Transducing - metabolism
/ Design
/ DNA-Binding Proteins - chemistry
/ DNA-Binding Proteins - metabolism
/ E coli
/ Escherichia coli - metabolism
/ Glues
/ Humanities and Social Sciences
/ Humans
/ Proteins
/ Science
/ Thalidomide - analogs & derivatives
