Structural basis of cellular dNTP regulation by SAMHD1

Significance SAMHD1 is a dNTPase that depletes the cellular dNTP pool to inhibit the replication of retroviruses, including HIV-1. The dNTPase activity of SAMHD1 also enables the enzyme to be a major regulator of cellular dNTP levels in mammalian cells, in addition to be implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and Aicardi Goutières syndrome (AGS). Here we present extensive structural and enzymatic data to reveal how SAMHD1 is activated and regulated via the combined actions of GTP and all cellular dNTPs. Our work establishes a complete spectrum of nucleotide binding and the exquisite regulatory mechanism of SAMHD1 in cellular dNTP metabolism, retrovirus restriction, and the pathogenesis of CLL and AGS.