9B9H

Crystal structure of the ternary complex of DCAF1 and WDR5 with PROTAC, OICR-40333

これはPDB形式変換不可エントリーです。

9B9H の概要

• エントリーDOI: 10.2210/pdb9b9h/pdb
• 分子名称: DDB1- and CUL4-associated factor 1, WD repeat-containing protein 5, N-{(1P)-5'-({(17E)-18-[(3P)-4-{[(1S)-3-amino-1-(3-chloro-4-fluorophenyl)-3-oxopropyl]carbamoyl}-3-(4-chloro-2-fluorophenyl)-1H-pyrrol-2-yl]-16-oxo-3,6,9,12-tetraoxa-15-azaoctadec-17-en-1-yl}carbamoyl)-2'-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl][1,1'-biphenyl]-3-yl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: e3 ligase, adaptor, protac, wdr, ternary complex, protein binding
• 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: 75987.12

構造登録者

Mabanglo, M.F.,Wilson, B.J.,Alvarez, H.G.,Hoffer, L.,Al-awar, R.,Vedadi, M. (登録日: 2024-04-02, 公開日: 2024-11-06, 最終更新日: 2024-12-04)

主引用文献

Mabanglo, M.F.,Wilson, B.,Noureldin, M.,Kimani, S.W.,Mamai, A.,Krausser, C.,Gonzalez-Alvarez, H.,Srivastava, S.,Mohammed, M.,Hoffer, L.,Chan, M.,Avrumutsoae, J.,Li, A.S.M.,Hajian, T.,Tucker, S.,Green, S.,Szewczyk, M.,Barsyte-Lovejoy, D.,Santhakumar, V.,Ackloo, S.,Loppnau, P.,Li, Y.,Seitova, A.,Kiyota, T.,Wang, J.G.,Prive, G.G.,Kuntz, D.A.,Patel, B.,Rathod, V.,Vala, A.,Rout, B.,Aman, A.,Poda, G.,Uehling, D.,Ramnauth, J.,Halabelian, L.,Marcellus, R.,Al-Awar, R.,Vedadi, M.
Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity.
Nat Commun, 15:10165-10165, 2024

PubMed Abstract: Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 ligases with diverse sets of substrates.

PubMed: 39580491
DOI: 10.1038/s41467-024-54500-x

実験手法

X-RAY DIFFRACTION (2.06 Å)