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Molecular basis for human aquaporin inhibition

Huang, Peng LU ; Åbacka, Hannah LU orcid ; Wilson, Carter J ; Wind, Malene Lykke ; Rűtzler, Michael ; Hagström-Andersson, Anna LU orcid ; Gourdon, Pontus LU ; de Groot, Bert L ; Venskutonytė, Raminta LU and Lindkvist-Petersson, Karin LU (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
; ; ; ; ; ; ; ; and
organization
publishing date
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}},
}