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- EMDB-20691: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Filament ... -

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Basic information

Entry
Database: EMDB / ID: EMD-20691
TitleHuman IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Filament assembly interface reconstruction.
Map dataHuman IMPDH2 treated with ATP, IMP, NAD , and 2 mM GTP. Filament assembly interface reconstruction.
Sample
  • Organelle or cellular component: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Fully compressed filament segment reconstruction.
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
Keywordsmetabolism / filament / allostery / adenine / guanine / BIOSYNTHETIC PROTEIN
Function / homology
Function and homology information


'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / lymphocyte proliferation / IMP dehydrogenase / IMP dehydrogenase activity / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 ...'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / lymphocyte proliferation / IMP dehydrogenase / IMP dehydrogenase activity / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 / circadian rhythm / secretory granule lumen / ficolin-1-rich granule lumen / Potential therapeutics for SARS / nucleotide binding / Neutrophil degranulation / DNA binding / RNA binding / extracellular exosome / extracellular region / metal ion binding / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase signature. / Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase/GMP reductase / IMP dehydrogenase / GMP reductase domain / 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: 3.14 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 5, 2019-
Header (metadata) releaseSep 18, 2019-
Map releaseMar 25, 2020-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 17
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 17
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6u8s
  • Surface level: 17
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20691.png

Downloads & links

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Map

FileDownload / File: emd_20691.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. Filament assembly interface 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

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 17.0 / Movie #1: 17
Minimum - Maximum-50.380253000000003 - 73.648210000000006
Average (Standard dev.)0.054045495 (±2.056925)
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-50.38073.6480.054

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Supplemental data

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Mask #1

Fileemd_20691_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_20691_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_20691_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Fully com...

EntireName: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Fully compressed filament segment reconstruction.
Components
  • Organelle or cellular component: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Fully compressed filament segment reconstruction.
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

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Supramolecule #1: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Fully com...

SupramoleculeName: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Fully compressed filament segment reconstruction.
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 8 / Enantiomer: LEVO / EC number: IMP dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.874863 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MADYLISGGT SYVPDDGLTA QQLFNCGDGL TYNDFLILPG YIDFTADQVD LTSALTKKIT LKTPLVSSPM DTVTEAGMAI AMALTGGIG FIHHNCTPEF QANEVRKVKK YEQGFITDPV VLSPKDRVRD VFEAKARHGF CGIPITDTGR MGSRLVGIIS S RDIDFLKE ...String:
MADYLISGGT SYVPDDGLTA QQLFNCGDGL TYNDFLILPG YIDFTADQVD LTSALTKKIT LKTPLVSSPM DTVTEAGMAI AMALTGGIG FIHHNCTPEF QANEVRKVKK YEQGFITDPV VLSPKDRVRD VFEAKARHGF CGIPITDTGR MGSRLVGIIS S RDIDFLKE EEHDCFLEEI MTKREDLVVA PAGITLKEAN EILQRSKKGK LPIVNEDDEL VAIIARTDLK KNRDYPLASK DA KKQLLCG AAIGTHEDDK YRLDLLAQAG VDVVVLDSSQ GNSIFQINMI KYIKDKYPNL QVIGGNVVTA AQAKNLIDAG VDA LRVGMG SGSICITQEV LACGRPQATA VYKVSEYARR FGVPVIADGG IQNVGHIAKA LALGASTVMM GSLLAATTEA PGEY FFSDG IRLKKYRGMG SLDAMDKHLS SQNRYFSEAD KIKVAQGVSG AVQDKGSIHK FVPYLIAGIQ HSCQDIGAKS LTQVR AMMY SGELKFEKRT SSAQVEGGVH SLHSYEKRLF

UniProtKB: Inosine-5'-monophosphate dehydrogenase 2

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Macromolecule #2: INOSINIC ACID

MacromoleculeName: INOSINIC ACID / type: ligand / ID: 2 / Number of copies: 8 / Formula: IMP
Molecular weightTheoretical: 348.206 Da
Chemical component information

ChemComp-I:
INOSINIC ACID

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Macromolecule #3: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 3 / Number of copies: 8 / Formula: NAD
Molecular weightTheoretical: 663.425 Da
Chemical component information

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

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

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Image processing

Startup modelType of model: EMDB MAP
Final reconstructionApplied symmetry - Point group: D4 (2x4 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 166384
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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