9OS2

Cryo-EM structure of the DDB1/CRBN-MRT-5702-G3BP2 ternary complex

これはPDB形式変換不可エントリーです。

9OS2 の概要

• エントリーDOI: 10.2210/pdb9os2/pdb
• EMDBエントリー: 70791
• 分子名称: Protein cereblon, DNA damage-binding protein 1, Ras GTPase-activating protein-binding protein 2, ... (5 entities in total)
• 機能のキーワード: molecular glue degrader, neo-substrate, cereblon, e3 ubiquitin ligase, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 279734.21

構造登録者

Quan, C.,Petzold, G.,Gainza, P.,Tsai, J.,Bunker, R.D.,Wiedmer, L.,Donckele, E.J. (登録日: 2025-05-23, 公開日: 2026-01-28, 最終更新日: 2026-04-01)

主引用文献

Annunziato, S.,Quan, C.,Donckele, E.J.,Lamberto, I.,Bunker, R.D.,Zlotosch, M.,Schwander, L.,Murthy, A.,Wiedmer, L.,Staehly, C.,Matysik, M.,Gilberto, S.,Kapsitidou, D.,Wible, D.,De Donatis, G.M.,Trenh, P.,SriRamaratnam, R.,Strande, V.,Lieberherr, R.,Lyon, D.,Steiner, D.,Silva, J.,Almeida, R.,Dolgikh, E.,DeMarco, B.,Tsai, J.,Sadok, A.,Zarayskiy, V.,Walter, M.,Tiedt, R.,Lumb, K.J.,Bonenfant, D.,Fasching, B.,Castle, J.C.,Townson, S.A.,Gainza, P.,Petzold, G.
Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry.
Nat.Struct.Mol.Biol., 33:479-487, 2026

PubMed Abstract: Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4-RING E3 ubiquitin ligase (CRL4), and recruit neosubstrates to an MGD-induced neosurface on the CRBN CULT domain through molecular mimicry of a natural CRBN degron. Here, we identify G3BP2 (Ras-GAP SH3 domain-binding protein 2), a neosubstrate that bypasses canonical interactions with CRBN by engaging an unconventional binding site on the CRBN LON domain. The ternary complex interface does not resemble known interactions with CRBN. Instead, CRBN leverages a preexisting protein-protein interaction (PPI) hotspot on the target protein by mimicking an endogenous binding partner of G3BP2. Our findings suggest that composite neosurfaces that mimic and stabilize the footprint of natural PPIs (in short, 'glueprints') could become a viable strategy for the rational expansion of the MGD target repertoire.

PubMed: 41559416
DOI: 10.1038/s41594-025-01738-8

実験手法

ELECTRON MICROSCOPY (2.5 Å)