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- Title
Mechanism of allosteric activation of SAMHD1 by dGTP.
- Authors
Ji, Xiaoyun; Wu, Ying; Yan, Junpeng; Mehrens, Jennifer; Yang, Haitao; DeLucia, Maria; Hao, Caili; Gronenborn, Angela M; Skowronski, Jacek; Ahn, Jinwoo; Xiong, Yong
- Abstract
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.
- Publication
Nature structural & molecular biology, 2013, Vol 20, Issue 11, p1304
- ISSN
1545-9985
- Publication type
Journal Article
- DOI
10.1038/nsmb.2692