8K62

Crystal structure of ALKBH1 and 13h complex.

Summary for 8K62

• Entry DOI: 10.2210/pdb8k62/pdb
• Descriptor: Nucleic acid dioxygenase ALKBH1, MANGANESE (II) ION, 1-[5-[[3-(trifluoromethyloxy)phenyl]methoxy]pyrimidin-2-yl]pyrazole-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: inhibitor, dna 6ma demethylase, complex, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 44322.90

Authors

Liang, X.,Yinping, G.,Feng, L.,Jiang, Z.,Ke, X.,Shengyong, Y. (deposition date: 2023-07-24, release date: 2024-07-31, Last modification date: 2025-02-19)

Primary citation

Xiong, L.,Li, F.,Guo, Y.,Zhang, J.,Xu, K.,Xiong, Z.,Tong, A.,Li, L.,Yang, S.
Discovery of a Potent and Cell-Active Inhibitor of DNA 6mA Demethylase ALKBH1.
J.Am.Chem.Soc., 146:6992-7006, 2024

PubMed Abstract: -Methyladenine (6mA) of DNA has emerged as a novel epigenetic mark in eukaryotes, and several 6mA effector proteins have been identified. However, efforts to selectively inhibit the biological functions of these effector proteins with small molecules are unsuccessful to date. Here we report the first potent and selective small molecule inhibitor () of AlkB homologue 1 (ALKBH1), the only validated 6mA demethylase. showed an IC of 0.026 ± 0.013 μM and 1.39 ± 0.13 μM in the fluorescence polarization (FP) and enzyme activity assay, respectively, and a of 0.112 ± 0.017 μM in the isothermal titration calorimetry (ITC) assay. The potency of was well explained by the cocrystal structure of the -ALKBH1 complex. Furthermore, displayed excellent selectivity for ALKBH1. In cells, compound and its derivative were able to engage ALKBH1 and modulate the 6mA levels. Collectively, our study identified the first potent, isoform selective, and cell-active ALKBH1 inhibitor, providing a tool compound for exploring the biological functions of ALKBH1 and DNA 6mA.

PubMed: 38437718
DOI: 10.1021/jacs.4c00194

Experimental method

X-RAY DIFFRACTION (1.991 Å)