9WRI

Crystal structure of CtBP2 in complex with G9a

Summary for 9WRI

• Entry DOI: 10.2210/pdb9wri/pdb
• Descriptor: C-terminal-binding protein 2, Histone-lysine N-methyltransferase EHMT2, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: complex, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 77352.32

Authors

Zhang, B.,Jiang, J.,Sun, W.,Cai, Q.,Chen, S. (deposition date: 2025-09-12, release date: 2026-01-21)

Primary citation

Zhang, B.,Jiang, J.,Sun, W.,Hu, S.,Chen, P.,Li, L.,Jiang, M.,Chen, J.,Zeng, J.,Cai, D.,Luo, Q.,Liu, W.,Cai, Q.,Chen, S.
CtBP1/2 oligomerization promotes G9a-Mediated transcriptional repression.
J.Biol.Chem., 302:111063-111063, 2025

PubMed Abstract: Corepressors CtBP1 and CtBP2 (CtBP1/2) are evolutionarily conserved transcriptional regulators that repress gene expression by recruiting chromatin modifiers, yet the structural basis of this process remains elusive. Here, we identify a direct interaction between CtBP1/2 and the histone H3 lysine 9 (H3K9) methyltransferase G9a. Crystallographic and biochemical analyses reveal that a CtBP1/2 tetramer simultaneously engages two G9a molecules through a motif within the pre-SET domain of G9a, which is absent in its paralog GLP. This interaction enhances G9a catalytic activity in a manner strictly dependent on the oligomeric state of CtBP1/2. Disruption of CtBP2 tetramerization diminishes its association with G9a and abolishes enzymatic activation, underscoring the functional importance of CtBP1/2 oligomerization. In colorectal cancer (CRC) cells, CtBP2 and G9a co-occupy the PTEN promoter, where disruption of their interface reduces H3K9me2 deposition, derepresses PTEN expression, attenuates PI3K-AKT signaling, and impairs CRC cell proliferation. Together, these findings establish a structural framework for CtBP-mediated regulation of G9a activity and highlight the CtBP1/2-G9a complex as a potential therapeutic target in colorectal cancer.

PubMed: 41419197
DOI: 10.1016/j.jbc.2025.111063

Experimental method

X-RAY DIFFRACTION (1.85 Å)