CryoEM and computational modeling structural insights into the pH regulator NBCn1

Weiguang Wang, Hristina R. Zhekova, Kirill Tsirulnikov, B. Sridhar Dwadasi, Ehecatl Guzman Aparicio, Rustam Azimov, Natalia Abuladze, Liyo Kao, Dora Acuna, D. Peter Tieleman, Z. Hong Zhou, Alexander Pushkin and Ira Kurtz ()
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Weiguang Wang: University of California
Hristina R. Zhekova: University of Calgary
Kirill Tsirulnikov: University of California
B. Sridhar Dwadasi: University of Calgary
Ehecatl Guzman Aparicio: University of Calgary
Rustam Azimov: University of California
Natalia Abuladze: University of California
Liyo Kao: University of California
Dora Acuna: University of California
D. Peter Tieleman: University of Calgary
Z. Hong Zhou: University of California
Alexander Pushkin: University of California
Ira Kurtz: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Breast cancer cells survive despite being exposed to a toxic acidic extracellular environment, by utilizing the NBCn1 transporter. The molecular basis for this phenomenon is unknown, given the lack of an NBCn1 atomic structural model. We therefore determined the 3.3 Å cryoEM structure of the human NBCn1 outward facing (OF) conformational state with densities corresponding to the transported ions in the ion coordination site. We further generated NBCn1 inward facing (IF) and intermediate (occluded) structures and characterized the transport cycle and the ion dynamics in the IF and OF states. The results showed that NBCn1 utilizes an elevator-type transport mechanism with a small vertical shift of the ion coordination site between OF and IF conformational states and that the transported ions permeate without significant energy barriers. Functional experiments showed that NBCn1 has an extremely high ion turnover rate (TOR) of ~15,000 s−1. The unusually high NBCn1 TOR value associated with the small protein structural changes during the OF to IF transitions and the favorable ion permeation energetics provides breast cancer cells with a highly efficient base loading mechanism contributing to their survival advantage.

Date: 2025
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DOI: 10.1038/s41467-025-64868-z

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