4QG2

Crystal structure of the tetrameric GTP/dATP/ATP-bound SAMHD1 (RN206) mutant catalytic core

Summary for 4QG2

• Entry DOI: 10.2210/pdb4qg2/pdb
• Related: 4BZB 4QFX 4QFY 4QFZ 4QG0 4QG1 4QG4
• Descriptor: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, GUANOSINE-5'-TRIPHOSPHATE, 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: deoxynucleoside triphosphate triphosphohydrolase, 2'-deoxyadenosine-5'-triphosphate, guanosine-5'-triphosphate, hiv restriction factor, dntpase, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q9Y3Z3
• Total number of polymer chains: 4
• Total formula weight: 257860.17

Authors

Koharudin, L.M.I.,Wu, Y.,DeLucia, M.,Mehrens, J.,Gronenborn, A.M.,Ahn, J. (deposition date: 2014-05-22, release date: 2014-10-15, Last modification date: 2023-09-20)

Primary citation

Koharudin, L.M.,Wu, Y.,DeLucia, M.,Mehrens, J.,Gronenborn, A.M.,Ahn, J.
Structural Basis of Allosteric Activation of Sterile alpha Motif and Histidine-Aspartate Domain-containing Protein 1 (SAMHD1) by Nucleoside Triphosphates.
J.Biol.Chem., 289:32617-32627, 2014

PubMed Abstract: 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.

PubMed: 25288794
DOI: 10.1074/jbc.M114.591958

Experimental method

X-RAY DIFFRACTION (2.25 Å)