7QEI
Structure of human MTHFD2L in complex with TH7299
Summary for 7QEI
| Entry DOI | 10.2210/pdb7qei/pdb |
| Descriptor | Probable bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, (2S)-2-[[4-[[2,4-bis(azanyl)-6-oxidanylidene-1H-pyrimidin-5-yl]carbamoylamino]phenyl]carbonylamino]pentanedioic acid, 2'-MONOPHOSPHOADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total) |
| Functional Keywords | inhibitor, isoform, mthfd2l, 1c-metabolism, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33331.24 |
| Authors | Gustafsson, R.,Scaletti, E.R.,Stenmark, P. (deposition date: 2021-12-03, release date: 2022-10-12, Last modification date: 2024-11-13) |
| Primary citation | Scaletti, E.R.,Gustafsson Westergren, R.,Andersson, Y.,Wiita, E.,Henriksson, M.,Homan, E.J.,Jemth, A.S.,Helleday, T.,Stenmark, P. The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors. Chemmedchem, 17:e202200274-e202200274, 2022 Cited by PubMed Abstract: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors. PubMed: 35712863DOI: 10.1002/cmdc.202200274 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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