Molecular basis for human aquaporin inhibition.
Peng HuangHannah ÅbackaCarter J WilsonMalene Lykke WindMichael RűtzlerAnna Hagström-AnderssonPontus Emanuel GourdonBert L de GrootRaminta VenskutonytėKarin Lindkvist-PeterssonPublished in: Proceedings of the National Academy of Sciences of the United States of America (2024)
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-Å 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.
Keyphrases
- cell migration
- endothelial cells
- papillary thyroid
- poor prognosis
- end stage renal disease
- newly diagnosed
- squamous cell
- induced pluripotent stem cells
- ejection fraction
- molecular dynamics
- chronic kidney disease
- pluripotent stem cells
- prognostic factors
- binding protein
- signaling pathway
- squamous cell carcinoma
- long non coding rna
- vascular endothelial growth factor
- big data
- machine learning
- artificial intelligence
- single molecule
- electronic health record
- patient reported outcomes
- human health
- climate change