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- PDB-9mub: Human IMPDH2 mutant - S160del, treated with GTP, ATP, IMP, and NA... -

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Basic information

Entry
Database: PDB / ID: 9mub
TitleHuman IMPDH2 mutant - S160del, treated with GTP, ATP, IMP, and NAD+; tetramer reconstruction
ComponentsInosine-5'-monophosphate dehydrogenase 2
KeywordsOXIDOREDUCTASE / Dehydrogenase / purine biosynthesis
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 / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 ...lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / 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 / Potential therapeutics for SARS / ficolin-1-rich granule lumen / nucleotide binding / Neutrophil degranulation / DNA binding / RNA binding / extracellular exosome / extracellular region / membrane / metal ion binding / nucleus / 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
INOSINIC ACID / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Inosine-5'-monophosphate dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsO'Neill, A.G. / Kollman, J.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM149542 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM008268 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: An IMPDH2 variant associated with neurodevelopmental disorder disrupts purine biosynthesis and somite organization.
Authors: Audrey G O'Neill / Morgan E McCartney / Gavin M Wheeler / Jeet H Patel / Gardenia Sanchez-Ramirez / Justin M Kollman / Andrea E Wills /
Abstract: IMP dehydrogenase (IMPDH) controls a key regulatory node in purine biosynthesis. Gain-of-function mutations in human IMPDH2 are associated with neurodevelopmental disorders and neuromuscular symptoms ...IMP dehydrogenase (IMPDH) controls a key regulatory node in purine biosynthesis. Gain-of-function mutations in human IMPDH2 are associated with neurodevelopmental disorders and neuromuscular symptoms including dystonia, but the developmental mechanisms underlying these defects are unknown. We previously showed that these mutants are insensitive to GTP inhibition and hypothesized that their hyperactivity would affect nucleotide metabolism in vivo. Here, we characterize the metabolic and developmental consequences of the neurodevelopmental disorder-associated IMPDH2 mutant, S160del, in . We show that expressing S160del but not WT human IMPDH2 disrupts purine pools and somite organization in the developing tadpole. We also show that S160del disrupts in vivo IMPDH filament assembly, a well-described IMPDH regulatory mechanism. Cryo-EM structures show that S160del disrupts filament assembly by destabilizing the dimerization of regulatory Bateman domains. Dimerization of Bateman domains and subsequent filament formation can be restored with a high affinity ligand, but this does not restore sensitivity to GTP inhibition, suggesting S160del also disrupts allostery of IMPDH2 filaments. This work demonstrates that the structural effects of patient IMPDH2 variants can cause disruptions both to nucleotide levels and to the normal development of sensorimotor structures, helping us better understand the physiological basis of disease in these patients.
History
DepositionJan 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)229,62012
Polymers225,5744
Non-polymers4,0478
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Inosine-5'-monophosphate dehydrogenase 2 / IMP dehydrogenase 2 / IMPD 2 / IMPDH 2 / Inosine-5'-monophosphate dehydrogenase type II / IMP ...IMP dehydrogenase 2 / IMPD 2 / IMPDH 2 / Inosine-5'-monophosphate dehydrogenase type II / IMP dehydrogenase II / IMPDH-II


Mass: 56393.422 Da / Num. of mol.: 4 / Mutation: S160del
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-IMP / INOSINIC ACID


Mass: 348.206 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H13N4O8P / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Inosine 5'-monophosphate dehydrogenase 2 - S160del mutant, bound to GTP, ATP, IMP, and NAD+
Type: COMPLEX
Details: 5 uM enzyme was mixed with 1 mM ATP, 1 mM MgCl2, 20mM GTP, 1 mM IMP, and 300 uM NAD+.
Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 45000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 5 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2630

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 920210
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 259441 / Symmetry type: POINT
Atomic model buildingPDB-ID: 6UA5

6ua5


Accession code: 6UA5 / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00511236
ELECTRON MICROSCOPYf_angle_d0.915200
ELECTRON MICROSCOPYf_dihedral_angle_d8.2291552
ELECTRON MICROSCOPYf_chiral_restr0.0511756
ELECTRON MICROSCOPYf_plane_restr0.0071908

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