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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: EMD-4402
TitleElectron microscopy map of human IMPDH isoform 1 bound to GDP in 150 g/L Ficoll-70
Map data
Sample
  • Complex: filaments of human IMP dehydrogenase isoform 1 in complex with GDP
    • Protein or peptide: human IMP dehydrogenase isoform 1
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / negative staining / Resolution: 18.0 Å
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.
History
DepositionNov 5, 2018-
Header (metadata) releaseNov 14, 2018-
Map releaseJan 30, 2019-
UpdateMar 6, 2019-
Current statusMar 6, 2019Processing site: PDBe / Status: Released

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Structure visualization

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

emd_4402.png

Downloads & links

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Map

FileDownload / File: emd_4402.map.gz / Format: CCP4 / Size: 3.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 2.7 Å
Density
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.037048284 - 0.0514219
Average (Standard dev.)0.00085753016 (±0.01243262)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions100100100
Spacing100100100
CellA=B=C: 270.0 Å
α=β=γ: 90.0 °

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
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
Components
  • Complex: filaments of human IMP dehydrogenase isoform 1 in complex with GDP
    • Protein or peptide: human IMP dehydrogenase isoform 1

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Supramolecule #1: filaments of human IMP dehydrogenase isoform 1 in complex with GDP

SupramoleculeName: filaments of human IMP dehydrogenase isoform 1 in complex with GDP
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: The filaments are formed in the presence of macromolecular crowding conditions (150 g/L Ficoll-70)
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: human IMP dehydrogenase isoform 1

MacromoleculeName: human IMP dehydrogenase isoform 1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO / EC number: IMP dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: gshmadylis ggtgyvpedg ltaqqlfasa dgltyndfli lpgfidfiad evdltsaltr kitlktplis spmdtvtead maiamalmgg igfihhnctp efqanevrkv kkfeqgfitd pvvlspshtv gdvleakmrh gfsgipitet gtmgsklvgi vtsrdidfla ...String:
gshmadylis ggtgyvpedg ltaqqlfasa dgltyndfli lpgfidfiad evdltsaltr kitlktplis spmdtvtead maiamalmgg igfihhnctp efqanevrkv kkfeqgfitd pvvlspshtv gdvleakmrh gfsgipitet gtmgsklvgi vtsrdidfla ekdhttllse vmtprielvv apagvtlkea neilqrskkg klpivndcde lvaiiartdl kknrdyplas kdsqkqllcg aavgtreddk yrldlltqag vdvivldssq gnsvyqiamv hyikqkyphl qviggnvvta aqaknlidag vdglrvgmgc gsicitqevm acgrpqgtav ykvaeyarrf gvpiiadggi qtvghvvkal algastvmmg sllaatteap geyffsdgvr lkkyrgmgsl damekssssq kryfsegdkv kiaqgvsgsi qdkgsiqkfv pyliagiqhg cqdigarsls vlrsmmysge lkfekrtmsa qieggvhglh syekrly

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Experimental details

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Structure determination

Methodnegative staining
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

BufferpH: 8
StainingType: NEGATIVE / Material: Uranyl Acetate

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Electron microscopy

MicroscopeJEOL 1230
Electron beamAcceleration voltage: 100 kV / Electron source: TUNGSTEN HAIRPIN
Electron opticsC2 aperture diameter: 100.0 µm / Calibrated defocus max: 1.5 µm / Calibrated defocus min: 1.0 µm / Calibrated magnification: 54929 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.9 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 40000
Sample stageSpecimen holder model: JEOL
Image recordingFilm or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Digitization - Sampling interval: 15.6 µm / Number grids imaged: 1 / Number real images: 75 / Average exposure time: 1.0 sec. / Average electron dose: 20.0 e/Å2

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Image processing

Segment selectionNumber selected: 5384 / Software - Name: Xmipp (ver. 3.0)
CTF correctionSoftware - Name: CTFFIND (ver. 3)
Startup modelType of model: INSILICO MODEL / In silico model: Generated with IHRSR
Details: Horizontally pre-aligned using CL2D protocol implemented in Scipon/XMIPP software.
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 2.0) / Details: Random rot (after horizontal pre-alignment)
Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 97.2 Å
Applied symmetry - Helical parameters - Δ&Phi: -15.9 °
Applied symmetry - Helical parameters - Axial symmetry: C4 (4 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 18.0 Å / Resolution method: OTHER / Software - Name: RELION (ver. 2.0) / Number images used: 1860

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