7QEI

Structure of human MTHFD2L in complex with TH7299

7QEI の概要

• エントリーDOI: 10.2210/pdb7qei/pdb
• 分子名称: 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)
• 機能のキーワード: inhibitor, isoform, mthfd2l, 1c-metabolism, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33331.24

構造登録者

Gustafsson, R.,Scaletti, E.R.,Stenmark, P. (登録日: 2021-12-03, 公開日: 2022-10-12, 最終更新日: 2024-11-13)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (2.1 Å)