9V2W

Cryo-EM structure of the histone deacetylase complex Rpd3L in complex with di-nucleosome

Summary for 9V2W

• Entry DOI: 10.2210/pdb9v2w/pdb
• EMDB information: 64742
• Descriptor: Transcriptional regulatory protein SIN3, Transcriptional regulatory protein RXT2, Histone deacetylase complex subunit CTI6, ... (15 entities in total)
• Functional Keywords: histone deacetylase complex, histone modification, rpd3l, cryo-em, di-nucleosome, gene regulation/dna, gene regulation-dna complex
• Biological source: Saccharomyces cerevisiae S288C; More
• Total number of polymer chains: 26
• Total formula weight: 672918.54

Authors

Zhao, H.,Li, H.,Wang, C.,Yang, X.,Li, H.,Zou, B.,Dong, S.,Zhang, N.,Zhou, Y.,Yi, L.,Zhang, Y.,Xie, Y.,Qin, D.,Chao, W.,Pei, D.,He, J. (deposition date: 2025-05-21, release date: 2026-05-27, Last modification date: 2026-06-03)

Primary citation

Zhao, H.,Li, H.,Wang, C.,Yang, X.,Zou, B.,Dong, S.,Zhang, N.,Zhou, Y.,Yi, L.,Zhang, Y.,Xie, Y.,Qin, D.,Chao, W.C.H.,Pei, D.,He, J.
Chromatin context-dependent deacetylation by the asymmetric Rpd3L.
Nucleic Acids Res., 54:-, 2026

PubMed Abstract: The regulation of gene expression requires precise control of chromatin-associated complexes that respond to diverse structural and epigenetic cues. The Rpd3 Large (Rpd3L) complex is a Sin3 histone deacetylase complex (HDAC) that dynamically adapt to chromatin states to reinforce transcriptional silencing, yet the mechanisms governing the catalytic activation in chromatin context-dependent manner remain unclear. Here we present the cryo-electron microscopy structure of Rpd3L bound to both mono- and di-nucleosome substrate at near-atomic resolution, uncovering a substrate-guided allosteric activation mechanism. Rpd3L adopts an asymmetric architecture, in which the proximal catalytic module anchors the first nucleosome, while the Sin3 PAH domains engage linker DNA to reposition a second nucleosome. This spatial configuration brings the distal catalytic module into proximity with chromatin and unlocks its latent deacetylase activity. Biochemical and mass spectrometry analyses confirm that dual nucleosome engagement selectively enhances Rpd3L activity and broadens substrate specificity. Together, these findings establish a hierarchical mechanism by which Rpd3L interprets histone modifications and nucleosome organization to modulate its enzymatic output at promoter regions. Our study provides a framework for understanding higher-order chromatin repression mechanisms by chromatin-regulation complexes and co-repressors.

PubMed: 42152683
DOI: 10.1093/nar/gkag443

Experimental method

ELECTRON MICROSCOPY (3.4 Å)