Molecular basis for human aquaporin inhibition
(2024) In Proceedings of the National Academy of Sciences of the United States of America 121(7).- Abstract
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... (More)
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.
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- author
- Huang, Peng LU ; Åbacka, Hannah LU ; Wilson, Carter J ; Wind, Malene Lykke ; Rűtzler, Michael ; Hagström-Andersson, Anna LU ; Gourdon, Pontus LU ; de Groot, Bert L ; Venskutonytė, Raminta LU and Lindkvist-Petersson, Karin LU
- organization
- publishing date
- 2024-02-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Humans, Aquaporins/metabolism, Neoplasms, Aquaporin 1/metabolism
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 121
- issue
- 7
- article number
- e2319682121
- pages
- 8 pages
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:38319972
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.2319682121
- language
- English
- LU publication?
- yes
- id
- 0ad5fd66-0dda-4acc-a485-ab2cd2346e54
- date added to LUP
- 2024-02-21 13:46:22
- date last changed
- 2024-02-22 04:09:52
@article{0ad5fd66-0dda-4acc-a485-ab2cd2346e54, abstract = {{<p>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.</p>}}, author = {{Huang, Peng and Åbacka, Hannah and Wilson, Carter J and Wind, Malene Lykke and Rűtzler, Michael and Hagström-Andersson, Anna and Gourdon, Pontus and de Groot, Bert L and Venskutonytė, Raminta and Lindkvist-Petersson, Karin}}, issn = {{1091-6490}}, keywords = {{Humans; Aquaporins/metabolism; Neoplasms; Aquaporin 1/metabolism}}, language = {{eng}}, month = {{02}}, number = {{7}}, publisher = {{National Academy of Sciences}}, series = {{Proceedings of the National Academy of Sciences of the United States of America}}, title = {{Molecular basis for human aquaporin inhibition}}, url = {{http://dx.doi.org/10.1073/pnas.2319682121}}, doi = {{10.1073/pnas.2319682121}}, volume = {{121}}, year = {{2024}}, }