9Y9G

Cryo-EM structure of human CNNM4(K113A/R140A/R141A) tetramer with Magnesium and MgATP in outward-facing state

Summary for 9Y9G

• Entry DOI: 10.2210/pdb9y9g/pdb
• Related: 11GQ 9Y9D 9Y9F
• EMDB information: 72697
• Descriptor: Metal transporter CNNM4, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION (3 entities in total)
• Functional Keywords: magnesium transporter, membrane protein, transmembrane domain, ion binding, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 378058.92

Authors

Bai, Z.,Zhou, E.,Lu, W.,Du, J. (deposition date: 2025-09-14, release date: 2026-07-29, Last modification date: 2026-09-30)

Primary citation

Bai, Z.,Zhou, X.E.,Lu, W.,Du, J.
Dynamic dimer-of-dimers architecture defines Mg 2+ transport in human CNNM4.
Cell, 189:6097-, 2026

PubMed Abstract: Mg is essential for all living organisms, yet its transport across mammalian membranes remains poorly understood. Here, we present cryoelectron microscopy (cryo-EM) structures of a full-length mammalian Mg transporter on the plasma membrane, human CNNM4, in outward-facing and occluded states, revealing an unexpected tetrameric assembly organized as a dimer of asymmetric dimers-distinct from the symmetric dimers in prokaryotic homologs and long assumed for eukaryotic CNNMs. We show that Mg/ATP binding stabilizes the dynamic intracellular domains and promotes tetramerization, while an acidic patch binds additional Mg, potentially acting as a sensor to couple cytoplasmic Mg levels to transport activity. Within the transmembrane domain, a key glutamate flips upon Na binding and destabilizes the Mg-binding site in the outward-facing state, thereby promoting Mg/Na exchange. Together, these findings establish a mechanistic framework for CNNM transport and regulation that diverges from prokaryotic models and links CNNM function to human physiology and disease.

PubMed: 42497866
DOI: 10.1016/j.cell.2026.06.039

Experimental method

ELECTRON MICROSCOPY (3.89 Å)