9OUL

DDB1-CRBN with Ikaros(ZF2), SB-405483, and DEG-47: composite map and model submission

これはPDB形式変換不可エントリーです。

9OUL の概要

• エントリーDOI: 10.2210/pdb9oul/pdb
• EMDBエントリー: 70870
• 分子名称: DNA damage-binding protein 1, Protein cereblon, ZINC ION, ... (5 entities in total)
• 機能のキーワード: e3 ligases, cullin ring ligase, crl4, cereblon, crbn, molecular glues, imids, ligase, ikaros
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 145069.27

構造登録者

Rizvi, Z.,Lander, G.C. (登録日: 2025-05-28, 公開日: 2025-11-19, 最終更新日: 2026-03-25)

主引用文献

Dippon, V.N.,Rizvi, Z.,Choudhry, A.E.,Chung, C.W.,Alkuraya, I.F.,Xu, W.,Tao, X.B.,Jurewicz, A.J.,Schneck, J.L.,Chen, W.,Curnutt, N.M.,Kabir, F.,Chan, K.H.,Queisser, M.A.,Musetti, C.,Dai, H.,Lander, G.C.,Benowitz, A.B.,Woo, C.M.
Identification of an allosteric site on the E3 ligase adapter cereblon.
Nature, 651:482-490, 2026

PubMed Abstract: Cereblon (CRBN) is the target of thalidomide derivatives that achieve therapeutic efficacy against some haematologic neoplasias by recruiting neosubstrates for degradation. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBN to a novel CRBN and increasing the CRBN state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.

PubMed: 41565821
DOI: 10.1038/s41586-025-09994-w

実験手法

ELECTRON MICROSCOPY (2.97 Å)