8E6O

Crystal structure of human GCN5 histone acetyltransferase domain

Summary for 8E6O

• Entry DOI: 10.2210/pdb8e6o/pdb
• Descriptor: Histone acetyltransferase KAT2A, S-{(3S,5R,9R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]-3,5,9-trihydroxy-8,8-dimethyl-3,5,10,14-tetraoxo-2,4,6-trioxa-11,15-diaza-3lambda~5~,5lambda~5~-diphosphaheptadecan-17-yl} (2R)-2-hydroxypropanethioate (3 entities in total)
• Functional Keywords: histone acetyltransferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 60135.23

Authors

Lu, X.T.,Tao, Y.J. (deposition date: 2022-08-23, release date: 2024-02-28, Last modification date: 2025-08-27)

Primary citation

Zhu, R.,Ye, X.,Lu, X.,Xiao, L.,Yuan, M.,Zhao, H.,Guo, D.,Meng, Y.,Han, H.,Luo, S.,Wu, Q.,Jiang, X.,Xu, J.,Tang, Z.,Tao, Y.J.,Lu, Z.
ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion.
Cell Metab., 37:361-376.e7, 2025

PubMed Abstract: Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.

PubMed: 39561764
DOI: 10.1016/j.cmet.2024.10.015

Experimental method

X-RAY DIFFRACTION (2.37 Å)