Kinetic Analysis of the Inhibition of the NSD1, NSD2 and SETD2 Protein Lysine Methyltransferases by a K36M Oncohistone Peptide,ChemistrySelect

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Kinetic Analysis of the Inhibition of the NSD1, NSD2 and SETD2 Protein Lysine Methyltransferases by a K36M Oncohistone Peptide
ChemistrySelect ( IF 1.9 ) Pub Date : 2017-10-18 , DOI: 10.1002/slct.201701940
Maren Schuhmacher ₁ , Denis Kusevic ₁ , Srikanth Kudithipudi ₁ , Albert Jeltsch ₁

Affiliation

Methylation of histone 3 (H3) at lysine K36 is catalyzed by the NSD1, NSD2 and SETD2 protein lysine methyltransferases (PKMTs). In cancers, somatic K36M mutations were observed and shown to inhibit NSD2 and SETD2. We conducted a comparative steady‐state kinetic analysis of the inhibition of all three H3 K36 specific PKMTs by an inhibitory H3 (27‐43) peptide containing the K36M oncomutation. Our data show that NSD1 is also inhibited by the K36M mutation. With all three enzymes, we observed that the inhibition constant K_I is about 1.5 fold lower than the K_M for the corresponding substrate peptide indicating a better binding of the inhibitory peptide. This numerical similarity suggests a related mechanism of inhibition in all three cases in agreement with the conserved architecture of the active sites of these enzymes. The mechanism of inhibition of PKMTs by target lysine to methionine mutations is discussed.

中文翻译：

K36M瘤蛋白肽抑制NSD1，NSD2和SETD2蛋白赖氨酸甲基转移酶的动力学分析

NSD1，NSD2和SETD2蛋白赖氨酸甲基转移酶（PKMT）催化赖氨酸K36处组蛋白3（H3）的甲基化。在癌症中，观察到体细胞K36M突变并显示出抑制NSD2和SETD2的作用。我们对包含K36M抑制作用的抑制性H3（27-43）肽对所有三种H3 K36特异性PKMT的抑制作用进行了比较稳态动力学分析。我们的数据表明，NSD1也受到K36M突变的抑制。对于所有三种酶，我们观察到抑制常数K _I比K _M低约1.5倍对于相应的底物肽而言，表明抑制肽更好的结合。这种数值上的相似性表明，在所有这三种情况下，与这些酶活性位点的保守结构相一致的抑制作用的相关机制。讨论了靶赖氨酸对甲硫氨酸突变抑制PKMT的机制。

更新日期：2017-10-18

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