9Q2D

Cryo-EM structure of ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 (molecular glue degrader)

9Q2D の概要

• エントリーDOI: 10.2210/pdb9q2d/pdb
• 関連するPDBエントリー: 9Q22
• EMDBエントリー: 72160
• 分子名称: DNA-binding protein Ikaros, Protein cereblon, DNA damage-binding protein 1, ... (5 entities in total)
• 機能のキーワード: cereblon, degrader, ikaros, ikzf1, ddb1, molecular glue, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 157232.19

構造登録者

Zhu, J.,Pagarigan, B.E.,Tran, E.T. (登録日: 2025-08-15, 公開日: 2025-10-01, 最終更新日: 2025-10-22)

主引用文献

Luchini, G.,Liu, S.,Powers, H.L.,Cherney, E.,Zhu, J.,Danga, K.,Thompson, J.W.,Shi, L.,Pagarigan, B.,Wei, D.D.,Park, P.,Degnan, A.P.,Zapf, C.W.,Riggs, J.R.,Johnson, S.,Cummins, T.
Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues.
J.Med.Chem., 68:20657-20674, 2025

PubMed Abstract: Cullin-RING Ligase 4 Cereblon (CRL4) (CRBN) E3 ligase modulatory drugs (CELMoDs) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early immunomodulatory drugs (IMiDs) target Ikaros and Aiolos degradation. In addition, there are ongoing clinical trials targeting the degradation of biologically relevant proteins such as GSPT1, CK1α, and Helios with CRBN-based molecular glues. To date, most advanced preclinical and clinical CRBN-based molecular glues recruit their neosubstrates through canonical G-motifs, secondary protein features that are structurally similar but have significantly different amino acid sequence identities. Analogous to the development of kinase inhibitors, optimizing both neosubstrate recruitment and degradation selectivity is important to minimize potential off-target activity. Here, we describe a computational structure-based approach to analyze and predict putative ligand interactions important in the neosubstrate ternary complex. This approach provides valuable insights for enhanced designs toward the development of more selective and efficacious CRBN-based molecular glues.

PubMed: 40994183
DOI: 10.1021/acs.jmedchem.5c01919

実験手法

ELECTRON MICROSCOPY (2.94 Å)