Substrate-Assisted Inhibition of Ubiquitin-like Protein-Activating Enzymes: The NEDD8 E1 Inhibitor MLN4924 Forms a NEDD8-AMP Mimetic In Situ
Substrate-Assisted Inhibition of Ubiquitin-like Protein-Activating Enzymes: The NEDD8 E1 Inhibitor MLN4924 Forms a NEDD8-AMP Mimetic In Situ
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DOI：
10.1016/j.molcel.2009.12.024
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发表时间：
2010-01-15
期刊：
影响因子：
16
通讯作者：
Dick, Lawrence R.
中科院分区：
文献类型：
--
作者：
Brownell, James E.;Sintchak, Michael D.;Dick, Lawrence R.
NEDD8激活酶（NAE）启动了蛋白质稳态途径对于癌细胞生长和生存至关重要。 MLN4924是目前正在接受癌症治疗的NAE的选择性抑制剂。在这里，我们表明MLN4924是基于机制的NAE抑制剂，并创建了由酶催化的共价NEDD8-MLN4924加合物。 NEDD8-MLN4924加合物类似于NEDD8腺苷，这是NAE反应周期中的第一个中间体，但不能在随后的酶内反应中进一步使用。 NEDD8-MLN4924在NAE活性位点内加合的稳定性使酶活性阻止了酶活性，从而考虑了IVILN4924对NEDD8途径的有效抑制。重要的是，我们已经确定类似于MLN4924的化合物证明了与其他类似泛素样蛋白（UBL）形成类似的加合物的能力，这些蛋白质（UBL）由它们的同源激活酶催化。这些发现揭示了对E1S机制的见解，并提出了选择性抑制UBL共轭途径的一般策略。
The NEDD8-activating enzyme (NAE) initiates a protein homeostatic pathway essential for cancer cell growth and survival. MLN4924 is a selective inhibitor of NAE currently in clinical trials for the treatment of cancer. Here, we show that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by IVILN4924. Importantly, we have determined that compounds resembling MLN4924 demonstrate the ability to form analogous adducts with other ubiquitin-like proteins (UBLs) catalyzed by their cognate-activating enzymes. These findings reveal insights into the mechanism of E1s and suggest a general strategy for selective inhibition of UBL conjugation pathways.