Structural basis of allosteric activation of sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) by nucleoside triphosphates

J Biol Chem. 2014 Nov 21;289(47):32617-27. doi: 10.1074/jbc.M114.591958. Epub 2014 Oct 6.


Sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) plays a critical role in inhibiting HIV infection, curtailing the pool of dNTPs available for reverse transcription of the viral genome. Recent structural data suggested a compelling mechanism for the regulation of SAMHD1 enzymatic activity and revealed dGTP-induced association of two inactive dimers into an active tetrameric enzyme. Here, we present the crystal structures of SAMHD1 catalytic core (residues 113-626) tetramers, complexed with mixtures of nucleotides, including dGTP/dATP, dGTP/dCTP, dGTP/dTTP, and dGTP/dUTP. The combined structural and biochemical data provide insight into dNTP promiscuity at the secondary allosteric site and how enzymatic activity is modulated. In addition, we present biochemical analyses of GTP-induced SAMHD1 full-length tetramerization and the structure of SAMHD1 catalytic core tetramer in complex with GTP/dATP, revealing the structural basis of GTP-mediated SAMHD1 activation. Altogether, the data presented here advance our understanding of SAMHD1 function during cellular homeostasis.

Keywords: Enzyme Mechanism; Nucleic Acid; Protein Crystallization; SAM Domain and HD Domain-containing Protein 1 (SAMHD1); Structural Biology; X-ray Crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Catalytic Domain
  • Crystallography, X-Ray
  • Deoxyguanine Nucleotides / chemistry
  • Deoxyguanine Nucleotides / metabolism
  • Deoxyribonucleotides / chemistry*
  • Deoxyribonucleotides / metabolism
  • Humans
  • Models, Molecular
  • Monomeric GTP-Binding Proteins / chemistry*
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism
  • Mutation
  • Nucleic Acid Conformation
  • Nucleoside-Triphosphatase / chemistry*
  • Nucleoside-Triphosphatase / genetics
  • Nucleoside-Triphosphatase / metabolism
  • Protein Binding
  • Protein Multimerization*
  • Protein Structure, Tertiary
  • SAM Domain and HD Domain-Containing Protein 1


  • Deoxyguanine Nucleotides
  • Deoxyribonucleotides
  • deoxyguanosine triphosphate
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Nucleoside-Triphosphatase
  • Monomeric GTP-Binding Proteins

Associated data

  • PDB/4QFX
  • PDB/4QFY
  • PDB/4QFZ
  • PDB/4QG0
  • PDB/4QG1