1. Structural identification and comprehension of human ALDH1L1-Gossypol complex.
- Author
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Han CW, Lee HN, Jeong MS, Kim HY, and Jang SB
- Subjects
- Humans, NADP metabolism, NADP chemistry, Models, Molecular, Cryoelectron Microscopy, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms metabolism, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Aldehyde Oxidoreductases metabolism, Aldehyde Oxidoreductases chemistry, Protein Binding, Binding Sites, Allosteric Site, Protein Conformation, Cell Line, Tumor, Oxidoreductases Acting on CH-NH Group Donors, Gossypol chemistry, Gossypol pharmacology, Gossypol metabolism
- Abstract
The folate metabolism enzyme ALDH1L1 catalyzed 10-formyltetrahydrofolate to tetrahydrofolate and CO
2 . Non-small cell lung cancer cells (NSCLC) strongly express ALDH1L1. Gossypol binds to an allosteric site and disrupts the folate metabolism by preventing NADP+ binding. The Cryo-EM structures of tetrameric C-terminal aldehyde dehydrogenase human ALDH1L1 complex with gossypol were examined. Gossypol-bound ALDH1L1 interfered with NADP+ by shifting the allosteric site of the structural conformation, producing a closed-form NADP+ binding site. In addition, the inhibition activity of ALDH1L1 was targeted with gossypol in NSCLC. The gossypol treatment had anti-cancer effects on NSCLC by blocking NADPH and ATP production. These findings emphasize the structure characterizing ALDH1L1 with gossypol., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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