4RXQ: The Structure Of Gtp-dutp-bound Samhd1

Citation:
Abstract
SAMHD1 is the only known eukaryotic deoxynucleoside triphosphate triphosphohydrolase (dNTPase) and is a major regulator of intracellular dNTP pools. It has been reported to be a potent inhibitor of retroviruses such as HIV-1 and endogenous retrotransposons. Previous crystal structures have revealed that SAMHD1 is activated by dGTP-dependent tetramer formation. However, recent data have indicated that the primary activator of SAMHD1 is GTP, not dGTP. Therefore, how its dNTPase activity is regulated needs to be further clarified. Here, five crystal structures of the catalytic core of SAMHD1 in complex with different combinations of GTP and dNTPs are reported, including a GTP-bound dimer and four GTP/dNTP-bound tetramers. The data show that human SAMHD1 contains two unique activator-binding sites in the allosteric pocket. The primary activator GTP binds to one site and the substrate dNTP (dATP, dCTP, dUTP or dTTP) occupies the other. Consequently, both GTP and dNTP are required for tetramer activation of the enzyme. In the absence of substrate binding, SAMHD1 adopts an inactive dimer conformation even when complexed with GTP. Furthermore, SAMHD1 activation is regulated by the concentration of dNTP. Thus, the level of dNTP pools is elegantly regulated by the self-sensing ability of SAMHD1 through a novel activation mechanism.
PDB ID: 4RXQDownload
MMDB ID: 127690
PDB Deposition Date: 2014/12/11
Updated in MMDB: 2015/03
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4RXQ: tetrameric; determined by author and by software (PISA)
Molecular Components in 4RXQ
Label Count Molecule
Proteins (4 molecules)
4
Deoxynucleoside Triphosphate Triphosphohydrolase Samhd1(Gene symbol: SAMHD1)
Molecule annotation
Chemicals (16 molecules)
1
4
2
8
3
4
* Click molecule labels to explore molecular sequence information.

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