9GAO

Crystal structure of CRBNmidi in complex with 2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-methylacetamide

This is a non-PDB format compatible entry.

Summary for 9GAO

• Entry DOI: 10.2210/pdb9gao/pdb
• Related: 8RQ1 8RQ8 8RQA
• Descriptor: Protein cereblon, 2-[4-[(3~{R})-2,6-bis(oxidanylidene)piperidin-3-yl]phenoxy]-~{N}-methyl-ethanamide, ZINC ION, ... (4 entities in total)
• Functional Keywords: e3 ligase, protac, tpd, molecular glue, targeted protein degradation, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 75641.00

Authors

Rutter, Z.J.,Kroupova, A.,Zollman, D.,Ciulli, A. (deposition date: 2024-07-29, release date: 2024-10-02, Last modification date: 2024-10-30)

Primary citation

Kroupova, A.,Spiteri, V.A.,Rutter, Z.J.,Furihata, H.,Darren, D.,Ramachandran, S.,Chakraborti, S.,Haubrich, K.,Pethe, J.,Gonzales, D.,Wijaya, A.J.,Rodriguez-Rios, M.,Sturbaut, M.,Lynch, D.M.,Farnaby, W.,Nakasone, M.A.,Zollman, D.,Ciulli, A.
Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders.
Nat Commun, 15:8885-8885, 2024

PubMed 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 CRBN, a construct that readily expresses from E. coli with high yields as soluble, stable protein without DDB1. We benchmark CRBN 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 as an enabling tool to accelerate structure-based discovery of the next generation of CRBN based therapeutics.

PubMed: 39406745
DOI: 10.1038/s41467-024-52871-9

Experimental method

X-RAY DIFFRACTION (1.95 Å)