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- PDB-6uaj: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Free cano... -

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Basic information

Entry
Database: PDB / ID: 6uaj
TitleHuman IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Free canonical octamer reconstruction.
ComponentsInosine-5'-monophosphate dehydrogenase 2
KeywordsBIOSYNTHETIC PROTEIN / metabolism / filament / allostery / adenine / guanine
Function / homology
Function and homology information


lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase / IMP dehydrogenase activity / GMP biosynthetic process / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 / retina development in camera-type eye ...lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase / IMP dehydrogenase activity / GMP biosynthetic process / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 / retina development in camera-type eye / circadian rhythm / 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 signature. / IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase domain / IMP dehydrogenase/GMP reductase / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Aldolase-type TIM barrel
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / INOSINIC ACID / Inosine-5'-monophosphate dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.84 Å
AuthorsJohnson, M.C. / Kollman, J.M.
Funding support United States, 1items
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, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2020Provider: repository / Type: Initial release

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Assembly

Deposited unit
A: Inosine-5'-monophosphate dehydrogenase 2
B: Inosine-5'-monophosphate dehydrogenase 2
C: Inosine-5'-monophosphate dehydrogenase 2
D: Inosine-5'-monophosphate dehydrogenase 2
E: Inosine-5'-monophosphate dehydrogenase 2
F: Inosine-5'-monophosphate dehydrogenase 2
G: Inosine-5'-monophosphate dehydrogenase 2
H: Inosine-5'-monophosphate dehydrogenase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)472,36548
Polymers451,8448
Non-polymers20,52140
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Inosine-5'-monophosphate dehydrogenase 2 / IMPDH 2 / IMPDH-II


Mass: 56480.500 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IMPDH2, IMPD2 / Production host: Escherichia coli (E. coli) / References: UniProt: P12268, IMP dehydrogenase
#2: Chemical
ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE / Guanosine triphosphate


Mass: 523.180 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: GTP, energy-carrying molecule*YM
#3: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#4: Chemical
ChemComp-IMP / INOSINIC ACID / Inosinic acid


Mass: 348.206 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H13N4O8P / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human IMPDH2 treated with ATP, IMP, NAD+, and 2 mM GTP. Free canonical octamer reconstruction.
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 100 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14rc1_3161: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: D4 (2x4 fold dihedral)
3D reconstructionResolution: 3.84 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 31032 / Symmetry type: POINT

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