8RQ9

Crystal structure of PROTAC CFT-1297 in complex with CRBN-midi and BRD4(BD2)

これはPDB形式変換不可エントリーです。

8RQ9 の概要

• エントリーDOI: 10.2210/pdb8rq9/pdb
• 関連するPDBエントリー: 8RQ1 8RQ8 8RQA 8RQC
• 分子名称: Protein cereblon, Bromodomain-containing protein 4, (3~{S})-3-[7-[1-[7-[4-[6-(4-chlorophenyl)-1-methyl-spiro[[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4,1'-cyclopropane]-8-yl]pyrazol-1-yl]heptyl]piperidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]piperidine-2,6-dione, ... (5 entities in total)
• 機能のキーワード: e3 ligase, protac, tpd, targeted protein degradation, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 106857.91

構造登録者

Darren, D.,Ramachandran, S.,Kroupova, A.,Zollman, D.,Ciulli, A. (登録日: 2024-01-17, 公開日: 2024-09-25, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.91 Å)