SAMHD1, a deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase), prevents the infection of blood cells by retroviruses, including HIV, by depleting the cellular dNTP pool available for viral reverse transcription. SAMHD1 is a major regulator of cellular dNTP levels in mammalian cells. Mutations in SAMHD1 are associated with the autoimmune condition Aicardi Goutières Syndrome (AGS), whose clinical manifestations resemble congenital viral infection. The catalytic activity of SAMHD1 is regulated by allosteric binding of dGTP, which enables SAMHD1 monomers/dimers to assemble into the catalytically active tetrameric form. We have determined the crystal structure of the tetrameric human SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation via dGTP-induced assembly of the tetrameric complex from two inactive dimers. Intriguingly, GTP can also activate SAMHD1, and our data further show the binding promiscuity of other dNTPs at the allosteric site. These findings suggest a regulation system that may have a profound effect on the balancing of cellular dNTP pools. These results provide the basis for a mechanistic understanding of SAMHD1 function in HIV restriction, the pathogenesis of AGS, and regulation of cellular dNTP levels.

中文翻译：

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通过饥饿杀死 HIV——SAMHD1 的变构激活机制

SAMHD1 是一种脱氧核糖核苷三磷酸三磷酸水解酶 (dNTPase)，通过耗尽可用于病毒逆转录的细胞 dNTP 池来防止包括 HIV 在内的逆转录病毒感染血细胞。SAMHD1 是哺乳动物细胞中细胞 dNTP 水平的主要调节剂。SAMHD1 的突变与自身免疫性疾病 Aicardi Goutières 综合征 (AGS) 相关，其临床表现类似于先天性病毒感染。SAMHD1 的催化活性受 dGTP 的变构结合调节，这使得 SAMHD1 单体/二聚体能够组装成具有催化活性的四聚体形式。我们已经确定了四聚体人 SAMHD1-dGTP 复合物的晶体结构。该结构揭示了通过 dGTP 诱导的来自两个无活性二聚体的四聚体复合物组装的优雅变构机制。有趣的是，GTP 还可以激活 SAMHD1，我们的数据进一步显示了其他 dNTP 在变构位点的结合混杂性。这些发现表明了一个可能对细胞 dNTP 池的平衡产生深远影响的调节系统。这些结果为理解 SAMHD1 在 HIV 限制中的功能、AGS 的发病机制和细胞 dNTP 水平的调节提供了基础。