Molecular basis for human aquaporin inhibition

• 成果类型: Article
• 署名作者: Huang, Peng; Abacka, Hannah; Wilson, Carter J.; Wind, Malene Lykke; Rutzler, Michael; Hagstroem-Andersson, Anna; Gourdon, Pontus; de Groot, Bert L.; Venskutonyte, Raminta; Lindkvist-Petersson, Karin
• 署名单位: Lund University; University of Copenhagen; Lund University; Lund University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8663
• DOI: 10.1073/pnas.2319682121
• 发表日期: 2024-02-13
• 关键词: general force-field; x-ray-structure; protein; accurate

摘要

Cancer invasion and metastasis are known to be potentiated by the expression of aquaporins (AQPs). Likewise, the expression levels of AQPs have been shown to be prognostic for survival in patients and have a role in tumor growth, edema, angiogenesis, and tumor cell migration. Thus, AQPs are key players in cancer biology and potential targets for drug development. Here, we present the single- particle cryo- EM structure of human AQP7 at 3.2- angstrom resolution in complex with the specific inhibitor compound Z433927330. The structure in combination with MD simulations shows that the inhibitor binds to the endofacial side of AQP7. In addition, cancer cells treated with Z433927330 show reduced proliferation. The data presented here serve as a framework for the development of AQP inhibitors.