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- EMDB-48627: Human IMPDH2 mutant - S160del, treated with GTP, ATP, IMP, and NA... -

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Basic information

Entry
Database: EMDB / ID: EMD-48627
TitleHuman IMPDH2 mutant - S160del, treated with GTP, ATP, IMP, and NAD+; tetramer reconstruction
Map dataOutput from Phenix density modification, with blur_by_resolution_factor=5, used for model refinement
Sample
  • Complex: Inosine 5'-monophosphate dehydrogenase 2 - S160del mutant, bound to GTP, ATP, IMP, and NAD+
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
KeywordsDehydrogenase / purine biosynthesis / OXIDOREDUCTASE
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
Inosine-5'-monophosphate dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsO'Neill AG / Kollman JM
Funding support United States, 2 items
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, 2025-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateJun 17, 2026-
Current statusJun 17, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48627.png

Downloads & links

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Map

FileDownload / File: emd_48627.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationOutput from Phenix density modification, with blur_by_resolution_factor=5, used for model refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.89 Å/pix.
x 300 pix.
= 265.5 Å		0.89 Å/pix.
x 300 pix.
= 265.5 Å		0.89 Å/pix.
x 300 pix.
= 265.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.885 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.803
Minimum - Maximum-5.296464 - 10.873749999999999
Average (Standard dev.)0.00009080122 (±0.19613135)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 265.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_48627_msk_1.map
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Mask #2

Fileemd_48627_msk_2.map
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Additional map: Sharpened map from cryoSPARC NU refinement

Fileemd_48627_additional_1.map
AnnotationSharpened map from cryoSPARC NU refinement
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Additional map: Unsharpened map from cryoSPARC NU refinement

Fileemd_48627_additional_2.map
AnnotationUnsharpened map from cryoSPARC NU refinement
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Half map: Half map A from cryoSPARC NU refinement

Fileemd_48627_half_map_1.map
AnnotationHalf map A from cryoSPARC NU refinement
Projections & Slices
AxesZYX

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Histogram

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Half map: Half map B from cryoSPARC NU refinement

Fileemd_48627_half_map_2.map
AnnotationHalf map B from cryoSPARC NU refinement
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Sample components

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Entire : Inosine 5'-monophosphate dehydrogenase 2 - S160del mutant, bound ...

EntireName: Inosine 5'-monophosphate dehydrogenase 2 - S160del mutant, bound to GTP, ATP, IMP, and NAD+
Components
  • Complex: Inosine 5'-monophosphate dehydrogenase 2 - S160del mutant, bound to GTP, ATP, IMP, and NAD+
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

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Supramolecule #1: Inosine 5'-monophosphate dehydrogenase 2 - S160del mutant, bound ...

SupramoleculeName: Inosine 5'-monophosphate dehydrogenase 2 - S160del mutant, bound to GTP, ATP, IMP, and NAD+
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: 5 uM enzyme was mixed with 1 mM ATP, 1 mM MgCl2, 20mM GTP, 1 mM IMP, and 300 uM NAD+.
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Inosine-5'-monophosphate dehydrogenase 2

MacromoleculeName: Inosine-5'-monophosphate dehydrogenase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: IMP dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.393422 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SEFELMADYL ISGGTSYVPD DGLTAQQLFN CGDGLTYNDF LILPGYIDFT ADQVDLTSAL TKKITLKTPL VSSPMDTVTE AGMAIAMAL TGGIGFIHHN CTPEFQANEV RKVKKYEQGF ITDPVVLSPK DRVRDVFEAK ARHGFCGIPI TDTGRMGSRL V GIISRDID ...String:
SEFELMADYL ISGGTSYVPD DGLTAQQLFN CGDGLTYNDF LILPGYIDFT ADQVDLTSAL TKKITLKTPL VSSPMDTVTE AGMAIAMAL TGGIGFIHHN CTPEFQANEV RKVKKYEQGF ITDPVVLSPK DRVRDVFEAK ARHGFCGIPI TDTGRMGSRL V GIISRDID FLKEEEHDCF LEEIMTKRED LVVAPAGITL KEANEILQRS KKGKLPIVNE DDELVAIIAR TDLKKNRDYP LA SKDAKKQ LLCGAAIGTH EDDKYRLDLL AQAGVDVVVL DSSQGNSIFQ INMIKYIKDK YPNLQVIGGN VVTAAQAKNL IDA GVDALR VGMGSGSICI TQEVLACGRP QATAVYKVSE YARRFGVPVI ADGGIQNVGH IAKALALGAS TVMMGSLLAA TTEA PGEYF FSDGIRLKKY RGMGSLDAMD KHLSSQNRYF SEADKIKVAQ GVSGAVQDKG SIHKFVPYLI AGIQHSCQDI GAKSL TQVR AMMYSGELKF EKRTSSAQVE GGVHSLHSYE KRLF

UniProtKB: Inosine-5'-monophosphate dehydrogenase 2

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Macromolecule #2: INOSINIC ACID

MacromoleculeName: INOSINIC ACID / type: ligand / ID: 2 / Number of copies: 4 / Formula: IMP
Molecular weightTheoretical: 348.206 Da
Chemical component information

ChemComp-I:
INOSINIC ACID

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Macromolecule #3: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 3 / Number of copies: 4 / Formula: NAD
Molecular weightTheoretical: 663.425 Da
Chemical component information

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 2630 / Average exposure time: 5.0 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 45000

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Image processing

Particle selectionNumber selected: 920210
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 259441
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6ua5


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-9mub:
Human IMPDH2 mutant - S160del, treated with GTP, ATP, IMP, and NAD+; tetramer reconstruction

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