國家衛生研究院 NHRI:Item 3990099045/13616
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    题名: Xanthine derivatives reveal an allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2)
    作者: Lee, LC;Peng, YH;Chang, HH;Hsu, T;Lu, CT;Huang, CH;Hsueh, CC;Kung, FC;Kuo, CC;Jiaang, WT;Wu, SY
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: 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.
    日期: 2021-08-12
    關聯: Journal of Medicinal Chemistry. 2021 Aug 12;64(15):11288-11301.
    Link to: http://dx.doi.org/10.1021/acs.jmedchem.1c00663
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000685644300043
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85113623998
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