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- EMDB-70842: Human glutamine synthetase filament bound to ATP -

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Basic information

Entry
Database: EMDB / ID: EMD-70842
TitleHuman glutamine synthetase filament bound to ATP
Map dataATP bound human glutamine synthetase filament full
Sample
  • Complex: Glutamine synthetase filament complex bound to ATP
    • Protein or peptide: Glutamine synthetase
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsGlutamine synthetase / glutamate-ammonia ligase / filament / Type II / LIGASE
Function / homology
Function and homology information


intracellular ammonium homeostasis / protein S-acyltransferase / protein palmitoylation / Astrocytic Glutamate-Glutamine Uptake And Metabolism / protein-cysteine S-palmitoyltransferase activity / regulation of protein localization to nucleolus / regulation of sprouting angiogenesis / regulation of endothelial cell migration / glutamine synthetase / glutamine biosynthetic process ...intracellular ammonium homeostasis / protein S-acyltransferase / protein palmitoylation / Astrocytic Glutamate-Glutamine Uptake And Metabolism / protein-cysteine S-palmitoyltransferase activity / regulation of protein localization to nucleolus / regulation of sprouting angiogenesis / regulation of endothelial cell migration / glutamine synthetase / glutamine biosynthetic process / glutamine synthetase activity / Glutamate and glutamine metabolism / L-glutamate catabolic process / glial cell projection / response to glucose / positive regulation of erythrocyte differentiation / cellular response to starvation / ribosome biogenesis / cell body / angiogenesis / cell population proliferation / endoplasmic reticulum / mitochondrion / extracellular exosome / ATP binding / metal ion binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Glutamine synthetase, N-terminal conserved site / Glutamine synthetase signature 1. / Glutamine synthetase, beta-Grasp domain / Glutamine synthetase, glycine-rich site / Glutamine synthetase putative ATP-binding region signature. / Glutamine synthetase (GS) beta-grasp domain profile. / Glutamine synthetase, N-terminal domain superfamily / Glutamine synthetase, catalytic domain / Glutamine synthetase, N-terminal domain ...: / Glutamine synthetase, N-terminal conserved site / Glutamine synthetase signature 1. / Glutamine synthetase, beta-Grasp domain / Glutamine synthetase, glycine-rich site / Glutamine synthetase putative ATP-binding region signature. / Glutamine synthetase (GS) beta-grasp domain profile. / Glutamine synthetase, N-terminal domain superfamily / Glutamine synthetase, catalytic domain / Glutamine synthetase, N-terminal domain / Glutamine synthetase, catalytic domain / Glutamine synthetase (GS) catalytic domain profile. / Glutamine synthetase, catalytic domain / Glutamine synthetase/guanido kinase, catalytic domain
Similarity search - Domain/homology
Glutamine synthetase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.11 Å
AuthorsGreene ER / Muniz RS / Kollman JM / Fraser JS
Funding support United States, France, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1F32GM144981-01 United States
Human Frontier Science Program (HFSP)RGP0054 France
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM123159 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM145238 United States
CitationJournal: bioRxiv / Year: 2025
Title: Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity.
Authors: Eric Greene / Richard Muniz / Hiroki Yamamura / Samuel E Hoff / Priyanka Bajaj / D John Lee / Erin M Thompson / Angelika Arada / Gyun Min Lee / Massimiliano Bonomi / Justin M Kollman / James S Fraser /
Abstract: To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can ...To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a composite binding site formed at the filament interface by the product, glutamine. Time-resolved cryo-electron microscopy (cryo-EM) confirms that glutamine binding stabilizes these filaments, which in turn exhibit reduced catalytic specificity for ammonia at physiological concentrations. This inhibition appears induced by a conformational change that remodulates the active site loop ensemble gating substrate entry. Metadynamics ensemble refinement revealed >10 Å conformational range for the active site loop and that the loop is stabilized by transient contacts. This disorder is significant, as we show that the transient contacts which stabilize this loop in a closed conformation are essential for catalysis both and in cells. We propose that GS filament formation constitutes a negative-feedback mechanism, directly linking product concentration to the structural and functional remodeling of the enzyme.
History
DepositionMay 27, 2025-
Header (metadata) releaseJul 2, 2025-
Map releaseJul 2, 2025-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70842.png

Downloads & links

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Map

FileDownload / File: emd_70842.map.gz / Format: CCP4 / Size: 307.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationATP bound human glutamine synthetase filament full
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 432 pix.
= 364.176 Å		0.84 Å/pix.
x 432 pix.
= 364.176 Å		0.84 Å/pix.
x 432 pix.
= 364.176 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.843 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.33
Minimum - Maximum-1.5775318 - 3.2293952
Average (Standard dev.)-0.00029921098 (±0.07773466)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions432432432
Spacing432432432
CellA=B=C: 364.176 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: ATP bound human glutamine synthetase filament half B

Fileemd_70842_half_map_1.map
AnnotationATP bound human glutamine synthetase filament half B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: ATP bound human glutamine synthetase filament half A

Fileemd_70842_half_map_2.map
AnnotationATP bound human glutamine synthetase filament half A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Glutamine synthetase filament complex bound to ATP

EntireName: Glutamine synthetase filament complex bound to ATP
Components
  • Complex: Glutamine synthetase filament complex bound to ATP
    • Protein or peptide: Glutamine synthetase
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Glutamine synthetase filament complex bound to ATP

SupramoleculeName: Glutamine synthetase filament complex bound to ATP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Glutamine synthetase

MacromoleculeName: Glutamine synthetase / type: protein_or_peptide / ID: 1 / Number of copies: 20 / Enantiomer: LEVO / EC number: glutamine synthetase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.118402 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MTTSASSHLN KGIKQVYMSL PQGEKVQAMY IWIDGTGEGL RCKTRTLDSE PKCVEELPEW NFDGSSTLQS EGSNSDMYLV PAAMFRDPF RKDPNKLVLC EVFKYNRRPA ETNLRHTCKR IMDMVSNQHP WFGMEQEYTL MGTDGHPFGW PSNGFPGPQG P YYCGVGAD ...String:
MTTSASSHLN KGIKQVYMSL PQGEKVQAMY IWIDGTGEGL RCKTRTLDSE PKCVEELPEW NFDGSSTLQS EGSNSDMYLV PAAMFRDPF RKDPNKLVLC EVFKYNRRPA ETNLRHTCKR IMDMVSNQHP WFGMEQEYTL MGTDGHPFGW PSNGFPGPQG P YYCGVGAD RAYGRDIVEA HYRACLYAGV KIAGTNAEVM PAQWEFQIGP CEGISMGDHL WVARFILHRV CEDFGVIATF DP KPIPGNW NGAGCHTNFS TKAMREENGL KYIEEAIEKL SKRHQYHIRA YDPKGGLDNA RRLTGFHETS NINDFSAGVA NRS ASIRIP RTVGQEKKGY FEDRRPSANC DPFSVTEALI RTCLLNETGD EPFQYKN

UniProtKB: Glutamine synthetase

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 20 / 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: 40 / 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 statefilament

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Sample preparation

Concentration0.34 mg/mL
BufferpH: 7
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: D5 (2x5 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 2.11 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 310500
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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