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- PDB-8gb1: Crystal structure of SAMHD1 dimer bound to deoxyguanosine linked ... -

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Basic information

Entry
Database: PDB / ID: 8gb1
TitleCrystal structure of SAMHD1 dimer bound to deoxyguanosine linked inhibitor
ComponentsDeoxynucleoside triphosphate triphosphohydrolase SAMHD1
KeywordsHYDROLASE / SAMHD1 / dNTPase / inhibitor / deoxyguanosine linked inhibitor / hydrolase inhibitor / dimer / dimeric
Function / homology
Function and homology information


Nucleotide catabolism / Hydrolases; Acting on ester bonds; Triphosphoric-monoester hydrolases / deoxynucleoside triphosphate hydrolase activity / triphosphoric monoester hydrolase activity / dGTP binding / dATP catabolic process / dGTPase activity / tetraspanin-enriched microdomain / DNA strand resection involved in replication fork processing / deoxyribonucleotide catabolic process ...Nucleotide catabolism / Hydrolases; Acting on ester bonds; Triphosphoric-monoester hydrolases / deoxynucleoside triphosphate hydrolase activity / triphosphoric monoester hydrolase activity / dGTP binding / dATP catabolic process / dGTPase activity / tetraspanin-enriched microdomain / DNA strand resection involved in replication fork processing / deoxyribonucleotide catabolic process / dGTP catabolic process / negative regulation of type I interferon-mediated signaling pathway / regulation of innate immune response / somatic hypermutation of immunoglobulin genes / RNA nuclease activity / double-strand break repair via homologous recombination / Interferon alpha/beta signaling / site of double-strand break / single-stranded DNA binding / protein homotetramerization / defense response to virus / nucleic acid binding / immune response / innate immune response / DNA damage response / GTP binding / RNA binding / zinc ion binding / nucleoplasm / identical protein binding / nucleus / plasma membrane
Similarity search - Function
HD domain profile. / HD domain / HD domain / SAM domain (Sterile alpha motif) / SAM domain profile. / Metal dependent phosphohydrolases with conserved 'HD' motif. / Sterile alpha motif. / HD/PDEase domain / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily
Similarity search - Domain/homology
: / Chem-YWI / Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.46 Å
AuthorsEgleston, M. / Dong, L. / Howlader, A.H. / Bhat, S. / Orris, B. / Bianchet, M.A. / Greenberg, M.M. / Stivers, J.T.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM056834 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA233567 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM131736 United States
CitationJournal: Acs Chem.Biol. / Year: 2023
Title: Deoxyguanosine-Linked Bifunctional Inhibitor of SAMHD1 dNTPase Activity and Nucleic Acid Binding.
Authors: Egleston, M. / Dong, L. / Howlader, A.H. / Bhat, S. / Orris, B. / Bianchet, M.A. / Greenberg, M.M. / Stivers, J.T.
History
DepositionFeb 24, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
B: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
C: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
D: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)242,09512
Polymers239,2184
Non-polymers2,8778
Water11,169620
1
A: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
B: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,0476
Polymers119,6092
Non-polymers1,4394
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
D: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,0476
Polymers119,6092
Non-polymers1,4394
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.783, 144.040, 200.318
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein
Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 / dNTPase / Dendritic cell-derived IFNG-induced protein / DCIP / Monocyte protein 5 / MOP-5 / SAM ...dNTPase / Dendritic cell-derived IFNG-induced protein / DCIP / Monocyte protein 5 / MOP-5 / SAM domain and HD domain-containing protein 1 / hSAMHD1


Mass: 59804.383 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SAMHD1, MOP5 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9Y3Z3, Hydrolases; Acting on ester bonds; Triphosphoric-monoester hydrolases
#2: Chemical
ChemComp-YWI / 5'-O-[(R)-(3-{[(1M)-3'-bromo[1,1'-biphenyl]-3-carbonyl]amino}propoxy)(hydroxy)phosphoryl]-2'-deoxyguanosine


Mass: 663.414 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H28BrN6O8P
#3: Chemical
ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Fe
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 620 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.47 Å3/Da / Density % sol: 50.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 17% PEG3350, 0.15 M Ammonium citrate pH 7.3, 293 K, 5 mg/mL, 1 uL protein + 2 uL ML. Soak 1 uL of 1 mM compound

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 16, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.41→117.3 Å / Num. obs: 83225 / % possible obs: 96.29 % / Redundancy: 6.5 % / Biso Wilson estimate: 56.36 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.19 / Rpim(I) all: 0.081 / Net I/σ(I): 6.2
Reflection shellResolution: 2.41→2.56 Å / Redundancy: 6.9 % / Rmerge(I) obs: 2.76 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 8205 / CC1/2: 0.35 / Rpim(I) all: 0.94 / % possible all: 96.29

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Coot0.9.8model building
MOLREP11.9.02phasing
DIMPLEdata reduction
DIMPLEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.46→27.17 Å / SU ML: 0.331 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.4198
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2356 4357 2.73 %
Rwork0.1923 155096 -
obs0.1935 83212 96.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 75.24 Å2
Refinement stepCycle: LAST / Resolution: 2.46→27.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14705 0 172 620 15497
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003315241
X-RAY DIFFRACTIONf_angle_d0.678820584
X-RAY DIFFRACTIONf_chiral_restr0.04392175
X-RAY DIFFRACTIONf_plane_restr0.00892655
X-RAY DIFFRACTIONf_dihedral_angle_d6.67192140
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.46-2.490.33491410.3134870X-RAY DIFFRACTION90.55
2.49-2.520.30831520.30065297X-RAY DIFFRACTION99.16
2.52-2.550.31321450.31255319X-RAY DIFFRACTION99.08
2.55-2.580.31731490.29575305X-RAY DIFFRACTION99.6
2.58-2.620.35061490.28845353X-RAY DIFFRACTION99.75
2.62-2.650.3331480.27915389X-RAY DIFFRACTION99.89
2.65-2.690.28231550.2695343X-RAY DIFFRACTION99.89
2.69-2.730.27631520.25885403X-RAY DIFFRACTION99.93
2.73-2.770.29111480.25075313X-RAY DIFFRACTION100
2.77-2.820.30341580.25045434X-RAY DIFFRACTION100
2.82-2.870.30711470.24595282X-RAY DIFFRACTION99.98
2.87-2.920.31121490.25655371X-RAY DIFFRACTION100
2.92-2.980.2661530.23325372X-RAY DIFFRACTION100
2.98-3.040.30381490.2345366X-RAY DIFFRACTION99.95
3.04-3.10.24181490.23125333X-RAY DIFFRACTION100
3.1-3.170.29071500.23775411X-RAY DIFFRACTION99.98
3.17-3.250.3091500.2185411X-RAY DIFFRACTION100
3.25-3.340.23741490.22255288X-RAY DIFFRACTION99.98
3.34-3.440.27061310.21034805X-RAY DIFFRACTION89.23
3.47-3.550.2835950.20363677X-RAY DIFFRACTION91.38
3.55-3.670.18471320.18894660X-RAY DIFFRACTION90.71
3.69-3.820.24581410.1834650X-RAY DIFFRACTION93.74
3.82-40.26621110.16773945X-RAY DIFFRACTION73.09
4-4.210.181460.15365316X-RAY DIFFRACTION100
4.21-4.470.2121530.14445392X-RAY DIFFRACTION100
4.47-4.810.18811560.14025380X-RAY DIFFRACTION99.98
4.81-5.290.18531520.14465327X-RAY DIFFRACTION99.93
5.29-6.050.18971450.17385358X-RAY DIFFRACTION99.98
6.05-7.60.21961500.1845378X-RAY DIFFRACTION100
7.6-27.170.19431520.15625348X-RAY DIFFRACTION99.71

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