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Open data
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Basic information
Entry | Database: PDB / ID: 9dmu | ||||||||||||
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Title | Cryo-EM structure of IMPDH2 bound to IMP and GAD | ||||||||||||
![]() | Inosine-5'-monophosphate dehydrogenase 2 | ||||||||||||
![]() | OXIDOREDUCTASE / dehydrogenase / substrate / inhibitor | ||||||||||||
Function / homology | ![]() 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / lymphocyte proliferation / 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 / Purine ribonucleoside monophosphate biosynthesis / lymphocyte proliferation / 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 / Potential therapeutics for SARS / ficolin-1-rich granule lumen / nucleotide binding / Neutrophil degranulation / DNA binding / RNA binding / extracellular exosome / extracellular region / metal ion binding / nucleus / membrane / cytosol / cytoplasm Similarity search - Function | ||||||||||||
Biological species | ![]() | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 1.82 Å | ||||||||||||
![]() | Chen, Y.J. / Li, B. / Parada, L.F. | ||||||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 1.1 MB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 2.1 MB | Display | ![]() |
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Full document | ![]() | 2.1 MB | Display | |
Data in XML | ![]() | 97.8 KB | Display | |
Data in CIF | ![]() | 141.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 47016MC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 56233.242 Da / Num. of mol.: 8 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Chemical | ChemComp-IMP / #3: Chemical | ChemComp-A1A7T / [[( Mass: 746.557 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C25H30N7O14P2S / Feature type: SUBJECT OF INVESTIGATION #4: Chemical | ChemComp-K / #5: Water | ChemComp-HOH / | Has ligand of interest | Y | Has protein modification | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Ternary complex of IMPDH2 bound to IMP and GAD / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT | ||||||||||||||||||||
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Source (natural) | Organism: ![]() | ||||||||||||||||||||
Source (recombinant) | Organism: ![]() ![]() | ||||||||||||||||||||
Buffer solution | pH: 8 | ||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Specimen support | Details: PELCO easiGlow Glow Discharge Cleaning System / Grid material: GOLD / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 96 % / Chamber temperature: 289 K |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 29000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 600 nm |
Image recording | Electron dose: 66 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: D4 (2x4 fold dihedral) | ||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 1.82 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 876343 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6U8E Accession code: 6U8E / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||||||||||
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