7EHJ

human MTHFD2 in complex with compound 21, cofactor and phosphate.

Summary for 7EHJ

• Entry DOI: 10.2210/pdb7ehj/pdb
• Related: 7EHM 7EHN 7EHV
• Descriptor: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial, (2S)-2-[[4-[(4-azanyl-6-oxidanyl-pyrimidin-5-yl)carbamoylamino]phenyl]carbonylamino]pentanedioic acid, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: mthfd2, methylenetetrahydrofolate dehydrogenase 2, 1c metabolism, mitocondria, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70720.62

Authors

Lee, L.C.,Peng, Y.H.,Wu, S.Y. (deposition date: 2021-03-29, release date: 2021-08-11, Last modification date: 2023-11-29)

Primary citation

Lee, L.C.,Peng, Y.H.,Chang, H.H.,Hsu, T.,Lu, C.T.,Huang, C.H.,Hsueh, C.C.,Kung, F.C.,Kuo, C.C.,Jiaang, W.T.,Wu, S.Y.
Xanthine Derivatives Reveal an Allosteric Binding Site in Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2).
J.Med.Chem., 64:11288-11301, 2021

PubMed Abstract: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in one-carbon metabolism. The MTHFD2 gene is upregulated in various cancers but very low or undetectable in normal proliferating cells, and therefore a potential target for cancer treatment. In this study, we present the structure of MTHFD2 in complex with xanthine derivative , which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by . Allosteric inhibitors often provide good selectivity and, indeed, xanthine derivatives are highly selective for MTHFD2. Moreover, several conformational changes were observed upon the binding of , which impeded the binding of the cofactor and phosphate to MTHFD2. To the best of our knowledge, this is the first study to identify allosteric inhibitors targeting the MTHFD family and our results would provide insights on the inhibition mechanism of MTHFD proteins and the development of novel inhibitors.

PubMed: 34337952
DOI: 10.1021/acs.jmedchem.1c00663

Experimental method

X-RAY DIFFRACTION (2.16 Å)