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- EMDB-72697: Cryo-EM structure of human CNNM4(K113A/R140A/R141A) tetramer with... -

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Basic information

Entry
Database: EMDB / ID: EMD-72697
TitleCryo-EM structure of human CNNM4(K113A/R140A/R141A) tetramer with Magnesium and MgATP in outward-facing state
Map data
Sample
  • Complex: CNNM4(K113A/R140A/R141A)/Mg/ATP tetramer
    • Protein or peptide: Metal transporter CNNM4
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsMagnesium transporter / membrane protein / transmembrane domain / ion binding / TRANSPORT PROTEIN
Function / homology
Function and homology information


sodium ion transmembrane transporter activity / biomineral tissue development / magnesium ion transport / magnesium ion homeostasis / intracellular monoatomic cation homeostasis / magnesium ion transmembrane transporter activity / visual perception / basolateral plasma membrane / protein-containing complex / plasma membrane
Similarity search - Function
: / Metal transporter CNNM4-like, immunoglobulin-like domain / Metal transporter CNNM2-like, C-terminal CNBH domain / Ancient conserved domain protein family / Cyclin M transmembrane N-terminal domain / CNNM, transmembrane domain / CNNM transmembrane domain profile. / Ion transporter-like, CBS domain / CBS domain superfamily / CBS domain ...: / Metal transporter CNNM4-like, immunoglobulin-like domain / Metal transporter CNNM2-like, C-terminal CNBH domain / Ancient conserved domain protein family / Cyclin M transmembrane N-terminal domain / CNNM, transmembrane domain / CNNM transmembrane domain profile. / Ion transporter-like, CBS domain / CBS domain superfamily / CBS domain / CBS domain / CBS domain profile. / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / RmlC-like jelly roll fold
Similarity search - Domain/homology
Metal transporter CNNM4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.89 Å
AuthorsBai Z / Zhou E / Lu W / Du J
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL153219 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS112363 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS111031 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS129804 United States
CitationJournal: Cell / Year: 2026
Title: Dynamic dimer-of-dimers architecture defines Mg transport in human CNNM4.
Authors: Zhiyong Bai / X Edward Zhou / Wei Lü / Juan Du /
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 ...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.
History
DepositionSep 14, 2025-
Header (metadata) releaseJul 29, 2026-
Map releaseJul 29, 2026-
UpdateSep 30, 2026-
Current statusSep 30, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72697.png

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Map

FileDownload / File: emd_72697.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 416 pix.
= 361.504 Å		0.87 Å/pix.
x 416 pix.
= 361.504 Å		0.87 Å/pix.
x 416 pix.
= 361.504 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.869 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.00283
Minimum - Maximum-0.0034788523 - 0.013415491
Average (Standard dev.)0.000043801738 (±0.0003292472)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 361.504 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_72697_additional_1.map
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Half map: #2

Fileemd_72697_half_map_1.map
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Half map: #1

Fileemd_72697_half_map_2.map
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Sample components

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Entire : CNNM4(K113A/R140A/R141A)/Mg/ATP tetramer

EntireName: CNNM4(K113A/R140A/R141A)/Mg/ATP tetramer
Components
  • Complex: CNNM4(K113A/R140A/R141A)/Mg/ATP tetramer
    • Protein or peptide: Metal transporter CNNM4
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: CNNM4(K113A/R140A/R141A)/Mg/ATP tetramer

SupramoleculeName: CNNM4(K113A/R140A/R141A)/Mg/ATP tetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Metal transporter CNNM4

MacromoleculeName: Metal transporter CNNM4 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.910328 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAPVGGGGRP VGGPARGRLL LAAPVLLVLL WALGARGQGS PQQGTIVGMR LASCNKSCGT NPDGIIFVSE GSTVNLRLYG YSLGNISSN LISFTEVDDA ETLHKSTSCL ELTADLVVQQ LVNVSRGNTS GVLVVLTKFL AASESMKLYA LCTRAQPDGP W LKWTDKDS ...String:
MAPVGGGGRP VGGPARGRLL LAAPVLLVLL WALGARGQGS PQQGTIVGMR LASCNKSCGT NPDGIIFVSE GSTVNLRLYG YSLGNISSN LISFTEVDDA ETLHKSTSCL ELTADLVVQQ LVNVSRGNTS GVLVVLTKFL AASESMKLYA LCTRAQPDGP W LKWTDKDS LLFMVEEPGR FLPLWLHILL ITVLLVLSGI FSGLNLGLMA LDPMELRIVQ NCGTEKERRY ARKIEPIRRK GN YLLCSLL LGNVLVNTSL TILLDNLIGS GLMAVASSTI GIVIFGEILP QALCSRHGLA VGANTILLTK FFMLLTFPLS FPI SKLLDF FLGQEIRTVY NREKLMEMLK VTEPYNDLVK EELNMIQGAL ELRTKTVEDI MTQLQDCFMI RSDAILDFNT MSEI MESGY TRIPVFEDEQ SNIVDILYVK DLAFVDPDDC TPLKTITRFY NHPVHFVFHD TKLDAMLEEF KKGKSHLAIV QKVNN EGEG DPFYEVLGLV TLEDVIEEII KSEILDESDM YTDNRSRKRV SEKNKRDFSA FKDADNELKV KISPQLLLAA HRFLAT EVS QFSPSLISEK ILLRLLKYPD VIQELKFDEH NKYYARHYLY TRNKPADYFI LILQGKVEVE AGKENMKFET GAFSYYG TM ALTSVPSDRS PAHPTPLSRS ASLSYPDRTD VSTAATLAGS SNQFGSSVLG QYISDFSVRA LVDLQYIKIT RQQYQNGL L ASRMENSPQF PIDGCTTHME NLAEKSELPV VDETTTLLNE RNSLLHKASH ENAIVDGSLE VLFQGPSGGS RLEEELRRR LTEGGSWSHP QFEKGGGSGG GSGGSAWSHP QFEKGSHHHH HHHH

UniProtKB: Metal transporter CNNM4

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 16 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.6 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.89 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5) / Number images used: 537678
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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