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Xanthine Derivatives Reveal an Allosteric Binding Site in Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2)
- Source :
- Journal of Medicinal Chemistry
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
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 15, which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by 15. 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 15, 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.
- Subjects :
- Models, Molecular
Allosteric regulation
Xanthine
Article
Cofactor
Structure-Activity Relationship
chemistry.chemical_compound
Downregulation and upregulation
Aminohydrolases
Drug Discovery
Humans
Enzyme Inhibitors
MTHFD2 Gene
Methylenetetrahydrofolate Dehydrogenase (NADP)
Dose-Response Relationship, Drug
Molecular Structure
biology
Substrate (chemistry)
Metabolism
Multifunctional Enzymes
Biochemistry
chemistry
biology.protein
Molecular Medicine
Uncompetitive inhibitor
Allosteric Site
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....cefd173f9bbcc3bc6e5f8b46d32a1935