Mechanism of allosteric activation of SAMHD1 by dGTP.

Publication Type:

Journal Article


Nat Struct Mol Biol, Volume 20, Issue 11, p.1304-9 (2013)


Allosteric Regulation, Binding Sites, Crystallography, X-Ray, Deoxyguanine Nucleotides, Humans, Models, Molecular, Monomeric GTP-Binding Proteins, Protein Conformation, Protein Multimerization, SAM Domain and HD Domain-Containing Protein 1


<p>SAMHD1, a dNTP triphosphohydrolase (dNTPase), has a key role in human innate immunity. It inhibits infection of blood cells by retroviruses, including HIV, and prevents the development of the autoinflammatory Aicardi-Goutières syndrome (AGS). The inactive apo-SAMHD1 interconverts between monomers and dimers, and in the presence of dGTP the protein assembles into catalytically active tetramers. Here, we present the crystal structure of the human tetrameric SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation through dGTP-induced tetramerization of two inactive dimers. Binding of dGTP to four allosteric sites promotes tetramerization and induces a conformational change in the substrate-binding pocket to yield the catalytically active enzyme. Structure-based biochemical and cell-based biological assays confirmed the proposed mechanism. The SAMHD1 tetramer structure provides the basis for a mechanistic understanding of its function in HIV restriction and the pathogenesis of AGS. </p>