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Open data
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Basic information
Entry | Database: PDB / ID: 6i0o | ||||||
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Title | Structure of human IMP dehydrogenase, isoform 2, bound to GTP | ||||||
![]() | Inosine-5'-monophosphate dehydrogenase 2 | ||||||
![]() | BIOSYNTHETIC PROTEIN / oxidoreductase / de novo guanine nucleotide biosynthesis | ||||||
Function / homology | ![]() 'de novo' XMP biosynthetic process / lymphocyte proliferation / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 ...'de novo' XMP biosynthetic process / lymphocyte proliferation / 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 / secretory granule lumen / ficolin-1-rich granule lumen / Potential therapeutics for SARS / nucleotide binding / Neutrophil degranulation / DNA binding / RNA binding / extracellular exosome / extracellular region / membrane / nucleus / metal ion binding / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Buey, R.M. / Fernandez-Justel, D. / Revuelta, J.L. | ||||||
Funding support | ![]()
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![]() | ![]() 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. | ||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 477.4 KB | Display | ![]() |
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PDB format | ![]() | 401.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 2.2 MB | Display | ![]() |
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Full document | ![]() | 2.2 MB | Display | |
Data in XML | ![]() | 35.6 KB | Display | |
Data in CIF | ![]() | 47.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 4402C ![]() 4403C ![]() 6i0mC ![]() 4z87S C: citing same article ( S: Starting model for refinement |
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Similar structure data |
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Assembly
Deposited unit | ![]()
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Unit cell |
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Components
#1: Protein | Mass: 56157.137 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Chemical | ChemComp-GTP / #3: Chemical | ChemComp-SO4 / #4: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 3.26 Å3/Da / Density % sol: 62.27 % |
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Crystal grow | Temperature: 295 K / Method: vapor diffusion, sitting drop Details: 25% (w/v) PEG-1500 0.1 M Buffer MIB (malonic acid, imadazole, boric acid), pH 9.0 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 21, 2015 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.99987 Å / Relative weight: 1 |
Reflection | Resolution: 2.623→81.953 Å / Num. obs: 44889 / % possible obs: 92.6 % / Redundancy: 6.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.142 / Rpim(I) all: 0.06 / Rrim(I) all: 0.155 / Net I/σ(I): 10.6 |
Reflection shell | Resolution: 2.623→2.827 Å / Redundancy: 7 % / Rmerge(I) obs: 1.564 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 353 / CC1/2: 0.408 / Rpim(I) all: 0.635 / Rrim(I) all: 1.689 / % possible all: 47 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 4Z87 Resolution: 2.623→81.953 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.37 / Stereochemistry target values: ML
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.623→81.953 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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