9OVR

CryoEM structural insight into the breast cancer pH regulator NBCn1

Summary for 9OVR

• Entry DOI: 10.2210/pdb9ovr/pdb
• EMDB information: 70906
• Descriptor: Sodium bicarbonate cotransporter 3, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, CARBONATE ION, ... (5 entities in total)
• Functional Keywords: transporter, sodium and carbonate cotransporter, ph regulator, breast cancers, protein transport
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 274955.06

Authors

Weiguang, W.,Hristina, R.Z.,Kirill, T.,Hong, Z.,Alexander, P.,Ira, K. (deposition date: 2025-05-30, release date: 2025-09-03, Last modification date: 2026-03-18)

Primary citation

Wang, W.,R Zhekova, H.,Tsirulnikov, K.,Dwadasi, B.S.,Aparicio, E.G.,Azimov, R.,Abuladze, N.,Kao, L.,Acuna, D.,Tieleman, D.P.,Zhou, Z.H.,Pushkin, A.,Kurtz, I.
CryoEM and computational modeling structural insights into the pH regulator NBCn1.
Nat Commun, 16:9932-9932, 2025

PubMed 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. 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.

PubMed: 41219199
DOI: 10.1038/s41467-025-64868-z

Experimental method

ELECTRON MICROSCOPY (3.3 Å)