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- EMDB-20705: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4... -

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Basic information

Entry
Database: EMDB / ID: EMD-20705
TitleHuman IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4 compressed, 1/4 extended) segment reconstruction.
Map dataHuman IMPDH2 treated with ATP, IMP, NAD , and 2 mM GTP. Bent (3/4 compressed, 1/4 extended) segment reconstruction.
Sample
  • Organelle or cellular component: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4 compressed, 1/4 extended) segment reconstruction.
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: GUANOSINE-5'-TRIPHOSPHATEGuanosine triphosphate
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
Function / homology
Function and homology information


lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 ...lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 / circadian rhythm / retina development in camera-type eye / Potential therapeutics for SARS / secretory granule lumen / ficolin-1-rich granule lumen / nucleotide binding / Neutrophil degranulation / RNA binding / DNA binding / extracellular exosome / extracellular region / membrane / metal ion binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase signature. / IMP dehydrogenase/GMP reductase / IMP dehydrogenase / GMP reductase domain / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Aldolase-type TIM barrel
Similarity search - Domain/homology
Inosine-5'-monophosphate dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.65 Å
AuthorsJohnson MC / Kollman JM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM118396-04 United States
CitationJournal: Elife / Year: 2020
Title: Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation.
Authors: Matthew C Johnson / Justin M Kollman /
Abstract: Inosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. IMPDH ...Inosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. IMPDH reversibly polymerizes in cells and tissues in response to changes in metabolic demand. Self-assembly of metabolic enzymes is increasingly recognized as a general mechanism for regulating activity, typically by stabilizing specific conformations of an enzyme, but the regulatory role of IMPDH filaments has remained unclear. Here, we report a series of human IMPDH2 cryo-EM structures in both active and inactive conformations. The structures define the mechanism of filament assembly, and reveal how filament-dependent allosteric regulation of IMPDH2 makes the enzyme less sensitive to feedback inhibition, explaining why assembly occurs under physiological conditions that require expansion of guanine nucleotide pools. Tuning sensitivity to an allosteric inhibitor distinguishes IMPDH from other metabolic filaments, and highlights the diversity of regulatory outcomes that can emerge from self-assembly.
History
DepositionSep 10, 2019-
Header (metadata) releaseNov 20, 2019-
Map releaseMar 25, 2020-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 10
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 10
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6ua4
  • Surface level: 10
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_20705.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman IMPDH2 treated with ATP, IMP, NAD , and 2 mM GTP. Bent (3/4 compressed, 1/4 extended) segment reconstruction.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 320 pix.
= 336. Å
1.05 Å/pix.
x 320 pix.
= 336. Å
1.05 Å/pix.
x 320 pix.
= 336. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density
Contour LevelBy AUTHOR: 0.1 / Movie #1: 10
Minimum - Maximum-69.18123 - 115.64215
Average (Standard dev.)0.07384094 (±2.9289212)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 336.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.051.051.05
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z336.000336.000336.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-69.181115.6420.074

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Supplemental data

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Mask #1

Fileemd_20705_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: half map 2

Fileemd_20705_half_map_1.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: half map 1

Fileemd_20705_half_map_2.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4...

EntireName: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4 compressed, 1/4 extended) segment reconstruction.
Components
  • Organelle or cellular component: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4 compressed, 1/4 extended) segment reconstruction.
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: GUANOSINE-5'-TRIPHOSPHATEGuanosine triphosphate
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

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Supramolecule #1: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4...

SupramoleculeName: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Bent (3/4 compressed, 1/4 extended) segment reconstruction.
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Inosine-5'-monophosphate dehydrogenase 2

MacromoleculeName: Inosine-5'-monophosphate dehydrogenase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 16 / Enantiomer: LEVO / EC number: IMP dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.4805 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SEFELMADYL ISGGTSYVPD DGLTAQQLFN CGDGLTYNDF LILPGYIDFT ADQVDLTSAL TKKITLKTPL VSSPMDTVTE AGMAIAMAL TGGIGFIHHN CTPEFQANEV RKVKKYEQGF ITDPVVLSPK DRVRDVFEAK ARHGFCGIPI TDTGRMGSRL V GIISSRDI ...String:
SEFELMADYL ISGGTSYVPD DGLTAQQLFN CGDGLTYNDF LILPGYIDFT ADQVDLTSAL TKKITLKTPL VSSPMDTVTE AGMAIAMAL TGGIGFIHHN CTPEFQANEV RKVKKYEQGF ITDPVVLSPK DRVRDVFEAK ARHGFCGIPI TDTGRMGSRL V GIISSRDI DFLKEEEHDC FLEEIMTKRE DLVVAPAGIT LKEANEILQR SKKGKLPIVN EDDELVAIIA RTDLKKNRDY PL ASKDAKK QLLCGAAIGT HEDDKYRLDL LAQAGVDVVV LDSSQGNSIF QINMIKYIKD KYPNLQVIGG NVVTAAQAKN LID AGVDAL RVGMGSGSIC ITQEVLACGR PQATAVYKVS EYARRFGVPV IADGGIQNVG HIAKALALGA STVMMGSLLA ATTE APGEY FFSDGIRLKK YRGMGSLDAM DKHLSSQNRY FSEADKIKVA QGVSGAVQDK GSIHKFVPYL IAGIQHSCQD IGAKS LTQV RAMMYSGELK FEKRTSSAQV EGGVHSLHSY EKRLF

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Macromolecule #2: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 12 / Formula: GTP
Molecular weightTheoretical: 523.18 Da
Chemical component information

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 10 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

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

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Macromolecule #4: INOSINIC ACID

MacromoleculeName: INOSINIC ACID / type: ligand / ID: 4 / Number of copies: 8 / Formula: IMP
Molecular weightTheoretical: 348.206 Da
Chemical component information

ChemComp-I:
INOSINIC ACID / Inosinic acid

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Macromolecule #5: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 5 / Number of copies: 8 / Formula: NAD
Molecular weightTheoretical: 663.425 Da
Chemical component information

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM / Nicotinamide adenine dinucleotide

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 100.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 31726
FSC plot (resolution estimation)

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