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- EMDB-47016: Cryo-EM structure of IMPDH2 bound to IMP and GAD -

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Basic information

Entry
Database: EMDB / ID: EMD-47016
TitleCryo-EM structure of IMPDH2 bound to IMP and GAD
Map datastructure of IMPDH2 bound to IMP and GAD
Sample
  • Complex: Ternary complex of IMPDH2 bound to IMP and GAD
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: INOSINIC ACID
  • Ligand: [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-[3-(thiophen-2-ylcarbonylamino)pyridin-1-yl]oxolan-2-yl]methyl hydrogen phosphate
  • Ligand: POTASSIUM ION
  • Ligand: water
Keywordsdehydrogenase / substrate / inhibitor / OXIDOREDUCTASE
Function / homology
Function and homology information


'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / lymphocyte proliferation / IMP dehydrogenase / IMP dehydrogenase activity / GMP biosynthetic process / Azathioprine ADME / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 ...'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / lymphocyte proliferation / 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 / ficolin-1-rich granule lumen / Potential therapeutics for SARS / nucleotide binding / Neutrophil degranulation / DNA binding / RNA binding / extracellular exosome / extracellular region / metal ion binding / nucleus / membrane / 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: 1.82 Å
AuthorsChen YJ / Li B / Parada LF
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA210100 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA196519-01 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA008748 United States
CitationJournal: Nature / Year: 2024
Title: Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.
Authors: Yu-Jung Chen / Swathi V Iyer / David Chun-Cheng Hsieh / Buren Li / Harold K Elias / Tao Wang / Jing Li / Mungunsarnai Ganbold / Michelle C Lien / Yu-Chun Peng / Xuanhua P Xie / Chenura D ...Authors: Yu-Jung Chen / Swathi V Iyer / David Chun-Cheng Hsieh / Buren Li / Harold K Elias / Tao Wang / Jing Li / Mungunsarnai Ganbold / Michelle C Lien / Yu-Chun Peng / Xuanhua P Xie / Chenura D Jayewickreme / Marcel R M van den Brink / Sean F Brady / S Kyun Lim / Luis F Parada /
Abstract: Glioblastoma is incurable and in urgent need of improved therapeutics. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. ...Glioblastoma is incurable and in urgent need of improved therapeutics. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD pocket. In vivo, gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.
History
DepositionSep 14, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateDec 25, 2024-
Current statusDec 25, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47016.png

Downloads & links

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Map

FileDownload / File: emd_47016.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of IMPDH2 bound to IMP and GAD
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 360 pix.
= 297.18 Å		0.83 Å/pix.
x 360 pix.
= 297.18 Å		0.83 Å/pix.
x 360 pix.
= 297.18 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8255 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-6.107682 - 16.970154000000001
Average (Standard dev.)0.00008154405 (±0.3311667)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 297.18 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_47016_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_47016_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of IMPDH2 bound to IMP and GAD

EntireName: Ternary complex of IMPDH2 bound to IMP and GAD
Components
  • Complex: Ternary complex of IMPDH2 bound to IMP and GAD
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase 2
  • Ligand: INOSINIC ACID
  • Ligand: [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-[3-(thiophen-2-ylcarbonylamino)pyridin-1-yl]oxolan-2-yl]methyl hydrogen phosphate
  • Ligand: POTASSIUM ION
  • Ligand: water

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Supramolecule #1: Ternary complex of IMPDH2 bound to IMP and GAD

SupramoleculeName: Ternary complex of IMPDH2 bound to IMP and GAD / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 8 / Enantiomer: LEVO / EC number: IMP dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.233242 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GSGRMADYLI SGGTSYVPDD GLTAQQLFNC GDGLTYNDFL ILPGYIDFTA DQVDLTSALT KKITLKTPLV SSPMDTVTEA GMAIAMALT GGIGFIHHNC TPEFQANEVR KVKKYEQGFI TDPVVLSPKD RVRDVFEAKA RHGFCGIPIT DTGRMGSRLV G IISSRDID ...String:
GSGRMADYLI SGGTSYVPDD GLTAQQLFNC GDGLTYNDFL ILPGYIDFTA DQVDLTSALT KKITLKTPLV SSPMDTVTEA GMAIAMALT GGIGFIHHNC TPEFQANEVR KVKKYEQGFI TDPVVLSPKD RVRDVFEAKA RHGFCGIPIT DTGRMGSRLV G IISSRDID 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: 8 / Formula: IMP
Molecular weightTheoretical: 348.206 Da
Chemical component information

ChemComp-I:
INOSINIC ACID

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Macromolecule #3: [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidany...

MacromoleculeName: [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-[3-(thiophen-2-ylcarbonylamino)pyridin- ...Name: [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-[3-(thiophen-2-ylcarbonylamino)pyridin-1-yl]oxolan-2-yl]methyl hydrogen phosphate
type: ligand / ID: 3 / Number of copies: 8 / Formula: A1A7T
Molecular weightTheoretical: 746.557 Da

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Macromolecule #4: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 4 / Number of copies: 8 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 756 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration1 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMTris-HCltris hydrochloride
150.0 mMKClpotassium chloride
1.0 mMTCEPtris(2-carboxyethyl)phosphine
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Pressure: 0.037 kPa / Details: PELCO easiGlow Glow Discharge Cleaning System
VitrificationCryogen name: ETHANE / Chamber humidity: 96 % / Chamber temperature: 289 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 66.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 29000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

20706

Final reconstructionApplied symmetry - Point group: D4 (2x4 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 1.82 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4) / Number images used: 876343
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6u8e


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9dmu:
Cryo-EM structure of IMPDH2 bound to IMP and GAD

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