Format

Send to:

Choose Destination
See comment in PubMed Commons below
Nat Struct Mol Biol. 2013 Nov;20(11):1304-9. doi: 10.1038/nsmb.2692. Epub 2013 Oct 20.

Mechanism of allosteric activation of SAMHD1 by dGTP.

Author information

  • 11] Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. [2].

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.

PMID:
24141705
[PubMed - indexed for MEDLINE]
PMCID:
PMC3833828
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Write to the Help Desk