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7QEI

Structure of human MTHFD2L in complex with TH7299

Summary for 7QEI
Entry DOI10.2210/pdb7qei/pdb
DescriptorProbable 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 Keywordsinhibitor, isoform, mthfd2l, 1c-metabolism, oxidoreductase
Biological sourceHomo sapiens (human)
Total number of polymer chains1
Total formula weight33331.24
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 citationScaletti, 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: 35712863
DOI: 10.1002/cmdc.202200274
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.1 Å)
Structure validation

239149

數據於2025-07-23公開中

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