TY - JOUR
T1 - Molecular basis for human aquaporin inhibition
AU - Huang, Peng
AU - Åbacka, Hannah
AU - Wilson, Carter J
AU - Wind, Malene Lykke
AU - Rűtzler, Michael
AU - Hagström-Andersson, Anna
AU - Gourdon, Pontus
AU - de Groot, Bert L
AU - Venskutonytė, Raminta
AU - Lindkvist-Petersson, Karin
PY - 2024/2/6
Y1 - 2024/2/6
N2 - 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.
AB - 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.
KW - Humans
KW - Aquaporins/metabolism
KW - Neoplasms
KW - Aquaporin 1/metabolism
U2 - 10.1073/pnas.2319682121
DO - 10.1073/pnas.2319682121
M3 - Article
C2 - 38319972
SN - 1091-6490
VL - 121
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
M1 - e2319682121
ER -
