User talk:Mousumi Kandangkel
From Proteopedia
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| - | == CryoEM and Computational Modeling Structural Insights into the pH Regulator NBCn1 (PDB 9OVR) == | + | <Structure load='9OVR' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />== CryoEM and Computational Modeling Structural Insights into the pH Regulator NBCn1 (PDB 9OVR) == |
=== Contents === | === Contents === | ||
Revision as of 17:10, 30 November 2025
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Contents |
Contents
1. Function
2. Structure of NBCn1
3. Mechanism of ion transport and pH regulation
4. Structural insights from cryoEM and modeling
5. Biological and medical implications
6. Key findings summary
Function
NBCn1 (SLC4A7) is an electroneutral Na⁺–bicarbonate cotransporter that imports base equivalents into cells to counteract acid production and maintain intracellular pH. Overexpression and high activity of NBCn1 in breast cancer cells support sustained cytosolic alkalinization, promoting proliferation and survival in an acidic tumor microenvironment.
Structure of NBCn1
The cryoEM structure of human NBCn1 (PDB: 9OVR) reveals a homodimer, with each protomer containing 14 transmembrane helices organized into a relatively rigid gate domain and a mobile core domain. The solved conformation is outward-facing, showing a wide extracellular vestibule leading to a central ion-binding region consistent with Na⁺–carbonate coordination.
Mechanism of ion transport and pH regulation
CryoEM density and modeling identify binding for two Na⁺ ions and one divalent anion, supporting a predominant 2Na⁺–CO₃²⁻ electroneutral symport mode that robustly imports base even when extracellular pH is low. This stoichiometry, together with intracellular buffering, explains how NBCn1 drives powerful net acid extrusion in breast cancer cells.
Structural insights from cryoEM and modeling
Molecular dynamics and free‑energy calculations support an elevator-type alternating access mechanism in which the core domain carrying the binding site shifts vertically by only about 5 Å relative to the gate domain. The small, well-coordinated movement creates alternating extracellular and intracellular access with low energy barriers, enabling an unusually high turnover rate of roughly 15,000 transport cycles per second.
Biological and medical implications
Structure‑guided cysteine scanning and mutagenesis of coordinating and pathway‑lining residues markedly reduce transport, directly linking specific structural elements to function. These maps, together with anti‑NBCn1 antibodies that block net acid extrusion and slow tumor growth, highlight NBCn1 as a promising, structurally tractable drug target in breast cancer.
Key findings summary
The NBCn1 structure shows how a dimeric 14‑TM elevator transporter can move large base fluxes through a compact, low‑motion ion‑binding core optimized for speed. By connecting architecture, transport stoichiometry, and tumor pH control, the study provides a detailed blueprint for designing inhibitors that selectively disable NBCn1‑mediated pH regulation in cancer cells.
