9DUR

Cryo-EM Structure of CRBN:dHTC1:ENL YEATS

これはPDB形式変換不可エントリーです。

9DUR の概要

• エントリーDOI: 10.2210/pdb9dur/pdb
• EMDBエントリー: 47174
• 分子名称: Protein cereblon, Protein ENL, ZINC ION, ... (4 entities in total)
• 機能のキーワード: mammalian, enl yeats, crbn, dhtc1, cip, 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: 2
• 化学式量合計: 74111.79

構造登録者

Cheong, H.,Hunkeler, M.,Fischer, E.S. (登録日: 2024-10-04, 公開日: 2025-11-19)

主引用文献

Shaum, J.B.,Munoz I Ordono, M.,Steen, E.A.,Wenge, D.V.,Cheong, H.,Hunkeler, M.,Bilotta, E.M.,Rutter, Z.,Barta, P.A.,Thornhill, A.M.,Milosevich, N.,Hargis, L.M.,Janowski, J.,Bishop, T.R.,Carter, T.R.,da Camara, B.,Hinterndorfer, M.,Dada, L.,He, W.J.,Offensperger, F.,Furihata, H.,Schweber, S.R.,Hatton, C.,Wen, Y.,Cravatt, B.F.,Engle, K.M.,Donovan, K.A.,Melillo, B.,Kitamura, S.,Ciulli, A.,Armstrong, S.A.,Fischer, E.S.,Winter, G.E.,Erb, M.A.
High-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity.
Biorxiv, 2025

PubMed Abstract: Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4 to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCF , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology.

PubMed: 40950085
DOI: 10.1101/2024.09.30.615685

実験手法

ELECTRON MICROSCOPY (2.9 Å)