The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
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DOI：
10.1038/s41467-018-07923-2
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发表时间：
2019-01
影响因子：
16.6
通讯作者：
Ee Lin Wong;Eric Nawrotzky;Christoph Arkona;Boo Geun Kim;Samuel Beligny;Xinning Wang;Stefan Wagner;M. Lisurek;D. Carstanjen;J. Rademann
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文献类型：
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作者：
Ee Lin Wong;Eric Nawrotzky;Christoph Arkona;Boo Geun Kim;Samuel Beligny;Xinning Wang;Stefan Wagner;M. Lisurek;D. Carstanjen;J. Rademann
蛋白质模板片段连接已成为一种组装和检测优化蛋白质配体的有效方法。该方法最初用于可逆连接，现已扩展到不可逆反应，从而形成超加性片段组合。在这里，蛋白质诱导的Mannich连接被发现是一种生物催化反应，提供转录因子STAT5的抑制剂。STAT5蛋白催化磷酸模拟物、甲醛和1h -四氮唑的多组分反应，产生的蛋白质配体具有极大的结合亲和力和配体效率。反应在生理条件下选择性地被天然STAT5诱导，而不是被其他蛋白质诱导。对结扎产物的形成和反应的（自）抑制进行了量化，并对其机理进行了研究。在急性髓性白血病（AML）细胞模型中，STAT5组装的抑制剂特异性地阻断了该蛋白的磷酸化，STAT5二聚体的dna结合，转录因子下游靶点的表达，以及小鼠癌细胞的增殖。
Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice.