CryoEM and computational modeling structural insights into the pH regulator NBCn1.
Weiguang Wang1,2, Hristina R Zhekova3, Kirill Tsirulnikov1
1Department of Medicine, Division of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Nature Communications
|November 11, 2025
Summary
Breast cancer cells survive acidic conditions using the NBCn1 transporter. Structural and functional studies reveal an efficient elevator mechanism and high turnover rate, aiding cancer cell survival.
Area of Science:
- Biochemistry
- Structural Biology
- Cancer Biology
Background:
- Breast cancer cells exhibit resistance to acidic extracellular environments.
- The NBCn1 transporter plays a crucial role in this survival mechanism.
- The atomic structure and transport mechanism of NBCn1 were previously unknown.
Purpose of the Study:
- To determine the cryo-electron microscopy (cryo-EM) structure of human NBCn1.
- To elucidate the transport mechanism and ion dynamics of NBCn1.
- To understand how NBCn1 contributes to breast cancer cell survival.
Main Methods:
- Determined the 3.3 Å cryo-EM structure of human NBCn1 in the outward-facing state.
- Generated inward-facing and intermediate NBCn1 structures.
- Performed functional experiments to characterize ion transport and turnover rate.
Main Results:
- Obtained the cryo-EM structure of human NBCn1, revealing ion densities in the coordination site.
- Elucidated an elevator-type transport mechanism with minimal structural changes between states.
- Demonstrated a high ion turnover rate (TOR) of approximately 15,000 s-1 for NBCn1.
Conclusions:
- NBCn1 utilizes an efficient elevator mechanism for ion transport.
- The high TOR and favorable energetics of NBCn1 facilitate base loading, enhancing breast cancer cell survival in acidic environments.
