Summary for 9DMU
| Entry DOI | 10.2210/pdb9dmu/pdb |
| EMDB information | 47016 |
| Descriptor | Inosine-5'-monophosphate dehydrogenase 2, INOSINIC ACID, [[(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, ... (5 entities in total) |
| Functional Keywords | dehydrogenase, substrate, inhibitor, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 8 |
| Total formula weight | 458936.82 |
| Authors | Chen, Y.J.,Li, B.,Parada, L.F. (deposition date: 2024-09-14, release date: 2024-11-27, Last modification date: 2024-12-25) |
| Primary citation | Chen, Y.J.,Iyer, S.V.,Hsieh, D.C.,Li, B.,Elias, H.K.,Wang, T.,Li, J.,Ganbold, M.,Lien, M.C.,Peng, Y.C.,Xie, X.P.,Jayewickreme, C.D.,van den Brink, M.R.M.,Brady, S.F.,Lim, S.K.,Parada, L.F. Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma. Nature, 636:466-473, 2024 Cited by PubMed 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. 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. PubMed: 39567689DOI: 10.1038/s41586-024-08224-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (1.82 Å) |
Structure validation
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