9W2F

Cryo-EM structure of DDB1-CRBN in complex with dHuR-2 and HuR

This is a non-PDB format compatible entry.

Summary for 9W2F

• Entry DOI: 10.2210/pdb9w2f/pdb
• EMDB information: 65569
• Descriptor: DNA damage-binding protein 1, Protein cereblon, ELAV-like protein 1, ... (5 entities in total)
• Functional Keywords: molecular glue degrader, complex, rna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 180844.39

Authors

Dou, H.,Zhu, Y. (deposition date: 2025-07-27, release date: 2026-04-22, Last modification date: 2026-06-24)

Primary citation

Lu, X.,Wang, X.,Yang, Z.,Wang, X.,Wang, L.,Xu, C.,Lo, I.C.,Geng, C.,Wang, L.,Pu, Y.,Zhang, K.,Zhu, Z.,Ye, L.,Huang, J.,Wei, X.,Bai, F.,Zhu, Y.,Qian, X.,Dou, H.,Su, H.,Cang, Y.
Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.
Nature, 2026

PubMed Abstract: BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC.

PubMed: 42271059
DOI: 10.1038/s41586-026-10613-5

Experimental method

ELECTRON MICROSCOPY (3.4 Å)