Kinetic Analysis of the Inhibition of the NSD1, NSD2 and SETD2 Protein Lysine Methyltransferases by a K36M Oncohistone Peptide
Kinetic Analysis of the Inhibition of the NSD1, NSD2 and SETD2 Protein Lysine Methyltransferases by a K36M Oncohistone Peptide
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K36M 肿瘤组蛋白肽抑制 NSD1、NSD2 和 SETD2 蛋白赖氨酸甲基转移酶的动力学分析
DOI：
10.1002/slct.201701940
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Kudithipudi S.Jeltsch A.
中科院分区：
文献类型：
--
作者：
Schuhmacher M.K;Kusevic D;Kudithipudi S.Jeltsch A.
组蛋白3(H3)在赖氨酸K36上的甲基化是由NSD1、NSD2和SETD2蛋白赖氨酸甲基转移酶(PKMT)催化的。在癌症中，体细胞K36M突变被观察到并被证明抑制了NSD2和SETD2。我们对含有K36M转位的抑制性H3(27-43)肽对所有三种H3 K36特异性PKMT的抑制进行了比较稳态的动力学分析。我们的数据显示，NSD1也受到K36M突变的抑制。对于这三种酶，我们观察到抑制常数KIIS比相应底物多肽的KM低约1.5倍，这表明抑制多肽有更好的结合。这种数值相似性表明，在所有三种情况下，都存在一种相关的抑制机制，这与这些酶的活性部位的保守结构相一致。对靶向赖氨酸抑制蛋氨酸突变的机制进行了讨论。
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 KIis about 1.5 fold lower than the KMfor 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.
影响因子：
10.5
作者：
Chan, Kui-Ming;Fang, Dong;Zhang, Zhiguo
通讯作者：
Zhang, Zhiguo
DOI：
10.1126/science.1232245
发表时间：
2013-05-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lewis PW;Müller MM;Koletsky MS;Cordero F;Lin S;Banaszynski LA;Garcia BA;Muir TW;Becher OJ;Allis CD
通讯作者：
Allis CD