9XTL

crystal structure of WDR5 with Histone H3 Q5E peptide

Summary for 9XTL

• Entry DOI: 10.2210/pdb9xtl/pdb
• Descriptor: WD repeat-containing protein 5, Histone H3.3 (3 entities in total)
• Functional Keywords: wdr5, histone h3, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 71258.78

Authors

Ye, X.L.,Zhao, H.,Xu, J. (deposition date: 2025-11-22, release date: 2026-09-30)

Primary citation

Guo, D.,Meng, Y.,Yang, Q.,Luo, S.,Jiang, X.,Zheng, Y.,Wu, L.,Li, S.,Jiang, H.,Li, S.,Wang, Z.,Li, M.,Wu, Q.,Xiao, L.,Zhu, R.,He, X.,Hu, Y.,Zhao, H.,Ye, X.,Tong, Y.,Fang, J.,Xu, D.,Xu, J.,Yuan, Y.,Lu, Z.
Lactate binds and inhibits the innate immune sensor STING to promote tumor immune evasion.
Immunity, 59:1811-1824.e7, 2026

PubMed Abstract: In cancer cells, pyruvate generated through aerobic glycolysis is preferentially converted into lactate. Here, we examined the impact of aerobic glycolysis on innate immune regulation within the tumor microenvironment. We identified lactate as a potent suppressor of stimulator of interferon genes (STING)-mediated innate immune signaling. Lactate directly bound the cyclic GMP-AMP (cGAMP)-binding domain of STING, thereby inhibiting cGAMP binding, STING activation, and interferon regulatory factor 3 (IRF3)-dependent cytokine expression. Mechanistically, activation of epidermal growth factor receptor (EGFR) promoted phosphorylation of lactate dehydrogenase A (LDHA) by pyruvate kinase M2 (PKM2) at serine 161 (S161). This increased LDHA activity and lactate production, which suppressed immune cell infiltration and promoted tumor growth. Pharmacological PKM2 inhibition relieved lactate-mediated STING suppression, reduced tumor immune evasion, and synergized with anti-PD-1 therapy. In human glioblastoma, elevated LDHA S161 phosphorylation correlated with reduced STING activation, diminished cytotoxic immune cell infiltration, and poor survival. Thus, oncogenic signaling directs PKM2-generated pyruvate toward LDHA-mediated lactate production, which directly inhibits STING to silence innate immune activation.

PubMed: 42379164
DOI: 10.1016/j.immuni.2026.06.004

Experimental method

X-RAY DIFFRACTION (2.06 Å)