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- EMDB-4402: Electron microscopy map of human IMPDH isoform 1 bound to GDP in ... -

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Basic information

Entry
Database: EMDB / ID: 4402
TitleElectron microscopy map of human IMPDH isoform 1 bound to GDP in 150 g/L Ficoll-70
Map data
Samplefilaments of human IMP dehydrogenase isoform 1 in complex with GDP:
human IMP dehydrogenase isoform 1
SourceHomo sapiens (human)
Methodhelical reconstruction / 18 Å resolution
AuthorsMartin-Benito J / Nunez R / Fernandez-Justel D / Revuelta JL / Buey RM
CitationJournal: J. Mol. Biol. / Year: 2019
Title: A Nucleotide-Dependent Conformational Switch Controls the Polymerization of Human IMP Dehydrogenases to Modulate their Catalytic Activity.
Authors: David Fernández-Justel / Rafael Núñez / Jaime Martín-Benito / David Jimeno / Adrián González-López / Eva María Soriano / José Luis Revuelta / Rubén M Buey
Abstract: Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH ...Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH has been studied for decades, but it has only been within the last years that we are starting to understand the complexity of the mechanisms of its physiological regulation. Here, we report structural and functional insights into how adenine and guanine nucleotides control a conformational switch that modulates the assembly of the two human IMPDH enzymes into cytoophidia and allosterically regulates their catalytic activity. In vitro reconstituted micron-length cytoophidia-like structures show catalytic activity comparable to unassembled IMPDH but, in turn, are more resistant to GTP/GDP allosteric inhibition. Therefore, IMPDH cytoophidia formation facilitates the accumulation of high levels of guanine nucleotides when the cell requires it. Finally, we demonstrate that most of the IMPDH retinopathy-associated mutations abrogate GTP/GDP-induced allosteric inhibition and alter cytoophidia dynamics.
DateDeposition: Nov 5, 2018 / Header (metadata) release: Nov 14, 2018 / Map release: Jan 30, 2019 / Last update: Jan 30, 2019

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_4402.map.gz (map file in CCP4 format, 4001 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
100 pix
2.7 Å/pix.
= 270. Å
100 pix
2.7 Å/pix.
= 270. Å
100 pix
2.7 Å/pix.
= 270. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 2.7 Å
Density
Contour Level:0.015 (by author), 0.015 (movie #1):
Minimum - Maximum-0.037048284 - 0.0514219
Average (Standard dev.)0.00085753016 (0.01243262)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions100100100
Origin0.00.00.0
Limit99.099.099.0
Spacing100100100
CellA=B=C: 270.0 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z2.72.72.7
M x/y/z100100100
origin x/y/z0.0000.0000.000
length x/y/z270.000270.000270.000
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS100100100
D min/max/mean-0.0370.0510.001

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Supplemental data

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Sample components

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Entire filaments of human IMP dehydrogenase isoform 1 in complex with GDP

EntireName: filaments of human IMP dehydrogenase isoform 1 in complex with GDP
Details: The filaments are formed in the presence of macromolecular crowding conditions (150 g/L Ficoll-70)
Number of components: 2

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Component #1: protein, filaments of human IMP dehydrogenase isoform 1 in comple...

ProteinName: filaments of human IMP dehydrogenase isoform 1 in complex with GDP
Details: The filaments are formed in the presence of macromolecular crowding conditions (150 g/L Ficoll-70)
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #2: protein, human IMP dehydrogenase isoform 1

ProteinName: human IMP dehydrogenase isoform 1 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Experimental details

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Sample preparation

SpecimenSpecimen state: helical array
Helical parametersAxial symmetry: C4 (4 fold cyclic) / Delta z: 97.2 Å / Delta phi: -15.9 deg.
Sample solutionpH: 8
VitrificationCryogen name: NONE

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Electron microscopy imaging

ImagingMicroscope: JEOL 1230
Electron gunElectron source: TUNGSTEN HAIRPIN / Accelerating voltage: 100 kV / Electron dose: 2 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 40000.0 X (nominal), 54929.0 X (calibrated) / Cs: 2.9 mm / Imaging mode: BRIGHT FIELD / Defocus: 1000.0 - 1500.0 nm
Specimen HolderModel: JEOL
CameraDetector: TVIPS TEMCAM-F416 (4k x 4k)

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Image acquisition

Image acquisitionNumber of digital images: 75 / Sampling size: 15.6 microns

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Image processing

ProcessingMethod: helical reconstruction
3D reconstructionSoftware: RELION / Resolution: 18 Å / Resolution method: OTHER / Euler angles: Random rot (after horizontal pre-alignment)

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