8RX0

(NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G76S, K48C)-UBE2R1(C93K, S138C, C191S, C223S)-Ub

8RX0 の概要

• エントリーDOI: 10.2210/pdb8rx0/pdb
• EMDBエントリー: 19567
• 分子名称: Isoform B of Bromodomain-containing protein 4, (2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[2-[2-[(9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]ethanoylamino]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-2,3-dihydro-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide, ZINC ION, ... (11 entities in total)
• 機能のキーワード: ubiquitin, cullin, ring, e2 complex, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 197623.28

構造登録者

Crowe, C.,Nakasone, M.A.,Ciulli, A. (登録日: 2024-02-05, 公開日: 2024-03-06, 最終更新日: 2025-12-24)

主引用文献

Crowe, C.,Nakasone, M.A.,Chandler, S.,Craigon, C.,Sathe, G.,Tatham, M.H.,Makukhin, N.,Hay, R.T.,Ciulli, A.
Mechanism of degrader-targeted protein ubiquitinability.
Sci Adv, 10:eado6492-eado6492, 2024

PubMed Abstract: Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4 toward UBE2R1-ubiquitin, and Lys at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4, with cellular degradation and ubiquitinomics confirming the importance of Lys and nearby Lys/Lys, identifying the "ubiquitination zone." Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.

PubMed: 39392888
DOI: 10.1126/sciadv.ado6492

実験手法

ELECTRON MICROSCOPY (3.7 Å)