4TNZ

Structure basis of cellular dNTP regulation, SAMHD1-GTP-dATP-dTTP complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.213 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Structural basis of cellular dNTP regulation by SAMHD1.

Ji, X.Tang, C.Zhao, Q.Wang, W.Xiong, Y.

(2014) Proc Natl Acad Sci U S A 111: E4305-E4314

  • DOI: https://doi.org/10.1073/pnas.1412289111
  • Primary Citation of Related Structures:  
    4TNP, 4TNQ, 4TNR, 4TNX, 4TNY, 4TNZ, 4TO0, 4TO1, 4TO2, 4TO3, 4TO4, 4TO5, 4TO6

  • PubMed Abstract: 

    The sterile alpha motif and HD domain-containing protein 1 (SAMHD1), a dNTPase, prevents the infection of nondividing cells by retroviruses, including HIV, by depleting the cellular dNTP pool available for viral reverse transcription. SAMHD1 is a major regulator of cellular dNTP levels in mammalian cells. Mutations in SAMHD1 are associated with chronic lymphocytic leukemia (CLL) and the autoimmune condition Aicardi Goutières syndrome (AGS). The dNTPase activity of SAMHD1 can be regulated by dGTP, with which SAMHD1 assembles into catalytically active tetramers. Here we present extensive biochemical and structural data that reveal an exquisite activation mechanism of SAMHD1 via combined action of both GTP and dNTPs. We obtained 26 crystal structures of SAMHD1 in complex with different combinations of GTP and dNTP mixtures, which depict the full spectrum of GTP/dNTP binding at the eight allosteric and four catalytic sites of the SAMHD1 tetramer. Our data demonstrate how SAMHD1 is activated by binding of GTP or dGTP at allosteric site 1 and a dNTP of any type at allosteric site 2. Our enzymatic assays further reveal a robust regulatory mechanism of SAMHD1 activity, which bares resemblance to that of the ribonuclease reductase responsible for cellular dNTP production. These results establish a complete framework for a mechanistic understanding of the important functions of SAMHD1 in the regulation of cellular dNTP levels, as well as in HIV restriction and the pathogenesis of CLL and AGS.


  • Organizational Affiliation

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Deoxynucleoside triphosphate triphosphohydrolase SAMHD1A [auth C],
B [auth A],
C [auth D],
D [auth B]
514Homo sapiensMutation(s): 2 
Gene Names: SAMHD1MOP5
EC: 3.1.5
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y3Z3 (Homo sapiens)
Explore Q9Y3Z3 
Go to UniProtKB:  Q9Y3Z3
PHAROS:  Q9Y3Z3
GTEx:  ENSG00000101347 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y3Z3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GTP
Query on GTP

Download Ideal Coordinates CCD File 
G [auth C],
N [auth A],
S [auth D],
X [auth B]
GUANOSINE-5'-TRIPHOSPHATE
C10 H16 N5 O14 P3
XKMLYUALXHKNFT-UUOKFMHZSA-N
DTP
Query on DTP

Download Ideal Coordinates CCD File 
H [auth C],
J [auth A],
T [auth D],
U [auth B]
2'-DEOXYADENOSINE 5'-TRIPHOSPHATE
C10 H16 N5 O12 P3
SUYVUBYJARFZHO-RRKCRQDMSA-N
TTP
Query on TTP

Download Ideal Coordinates CCD File 
E [auth C],
L [auth A],
Q [auth D],
V [auth B]
THYMIDINE-5'-TRIPHOSPHATE
C10 H17 N2 O14 P3
NHVNXKFIZYSCEB-XLPZGREQSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
F [auth C]
I [auth C]
K [auth A]
M [auth A]
O [auth A]
F [auth C],
I [auth C],
K [auth A],
M [auth A],
O [auth A],
P [auth D],
R [auth D],
W [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.213 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.126α = 90
b = 141.749β = 116.29
c = 98.474γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
PDB_EXTRACTdata extraction
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI097064

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-01
    Type: Initial release
  • Version 1.1: 2014-10-15
    Changes: Database references
  • Version 1.2: 2014-10-29
    Changes: Database references
  • Version 1.3: 2017-11-22
    Changes: Database references, Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary
  • Version 1.4: 2022-03-30
    Changes: Author supporting evidence, Database references, Derived calculations, Refinement description
  • Version 1.5: 2023-09-27
    Changes: Data collection, Refinement description