Molecular basis for human aquaporin inhibition-Reference-Cited by-同舟云学术

Molecular basis for human aquaporin inhibition

Published:2024-02-06 Issue:7 Volume:121 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Huang Peng¹^ORCID,Åbacka Hannah¹,Wilson Carter J.²,Wind Malene Lykke³,Rűtzler Michael⁴⁵,Hagström-Andersson Anna⁶,Gourdon Pontus¹³^ORCID,de Groot Bert L.²^ORCID,Venskutonytė Raminta¹⁷,Lindkvist-Petersson Karin¹⁷^ORCID

Affiliation:

1. Department of Experimental Medical Science, Lund University, Lund 22184, Sweden

2. Computational Biomolecular Dynamics Group, Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, 37077 Gottingen, Germany

3. Department of Biomedical Sciences, Copenhagen University, DK-2200 Copenhagen N, Denmark

4. ApoGlyx, Lund 22381, Sweden

5. Division of Biochemistry and Structural Biology, Department of Chemistry, Lund University, Lund 22100, Sweden

6. Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund 22184, Sweden

7. Lund Institute of Advanced Neutron and X-Ray Science, Lund 22370, Sweden

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 framework for the development of AQP inhibitors.

Funder

Swedish Research Council

Diabetesfonden

Cancerfonden

CSC | Chinese Government Scholarship

Publisher

Proceedings of the National Academy of Sciences

Link

https://pnas.org/doi/pdf/10.1073/pnas.2319682121

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