10DW

Structure of CRBN/DDB1dB-KAT2A-Compound4 ternary complex

This is a non-PDB format compatible entry.

Summary for 10DW

• Entry DOI: 10.2210/pdb10dw/pdb
• EMDB information: 75101
• Descriptor: Histone acetyltransferase KAT2A, Protein cereblon, DNA damage-binding protein 1, ... (5 entities in total)
• Functional Keywords: crbn, molecular glue, crbn-mg, kat2a, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 190716.21

Authors

Ojeda, S.,Fischer, E.S. (deposition date: 2026-01-14, release date: 2026-08-12)

Primary citation

Ojeda, S.,Wang, M.,Baek, K.,Bourgeois, W.,Sommerschield, A.,Yue, H.,Metivier, R.J.,Karagiannis, P.,Levitz, T.S.,Xiong, Y.,Donovan, K.A.,Armstrong, S.A.,Fischer, E.S.
Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.
Science, 393:188-194, 2026

PubMed Abstract: Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)-based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.

PubMed: 42424456
DOI: 10.1126/science.aef5391

Experimental method

ELECTRON MICROSCOPY (2.9 Å)