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- PDB-6dwk: SAMHD1 Bound to Fludarabine-TP in the Catalytic Pocket -

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Basic information

Entry
Database: PDB / ID: 6dwk
TitleSAMHD1 Bound to Fludarabine-TP in the Catalytic Pocket
ComponentsDeoxynucleoside triphosphate triphosphohydrolase SAMHD1
Keywordshydrolase/hydrolase inhibitor / Complex / deoxynucleoside triphosphate triphosphohydrolase / dNTPase / nucleotide analogue / Fludarabine-TP / HYDROLASE / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


Nucleotide catabolism / Hydrolases; Acting on ester bonds; Triphosphoric-monoester hydrolases / deoxynucleoside triphosphate hydrolase activity / dGTP binding / dATP catabolic process / deoxyribonucleotide catabolic process / tetraspanin-enriched microdomain / dGTPase activity / dGTP catabolic process / DNA strand resection involved in replication fork processing ...Nucleotide catabolism / Hydrolases; Acting on ester bonds; Triphosphoric-monoester hydrolases / deoxynucleoside triphosphate hydrolase activity / dGTP binding / dATP catabolic process / deoxyribonucleotide catabolic process / tetraspanin-enriched microdomain / dGTPase activity / dGTP catabolic process / DNA strand resection involved in replication fork processing / negative regulation of type I interferon-mediated signaling pathway / regulation of innate immune response / RNA nuclease activity / somatic hypermutation of immunoglobulin genes / double-strand break repair via homologous recombination / Interferon alpha/beta signaling / single-stranded DNA binding / site of double-strand break / 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
2'-DEOXYADENOSINE 5'-TRIPHOSPHATE / GLYCINE / GUANOSINE-5'-TRIPHOSPHATE / Chem-HFD / PHOSPHATE ION / Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.3 Å
AuthorsKnecht, K.M. / Buzovetsky, O. / Schneider, C. / Thomas, D. / Srikanth, V. / Kaderali, L. / Tofoleanu, F. / Reiss, K. / Ferreiros, N. / Geisslinger, G. ...Knecht, K.M. / Buzovetsky, O. / Schneider, C. / Thomas, D. / Srikanth, V. / Kaderali, L. / Tofoleanu, F. / Reiss, K. / Ferreiros, N. / Geisslinger, G. / Batista, V.S. / Ji, X. / Cinatl, J. / Keppler, O.T. / Xiong, Y.
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2018
Title: The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1.
Authors: Knecht, K.M. / Buzovetsky, O. / Schneider, C. / Thomas, D. / Srikanth, V. / Kaderali, L. / Tofoleanu, F. / Reiss, K. / Ferreiros, N. / Geisslinger, G. / Batista, V.S. / Ji, X. / Cinatl Jr., ...Authors: Knecht, K.M. / Buzovetsky, O. / Schneider, C. / Thomas, D. / Srikanth, V. / Kaderali, L. / Tofoleanu, F. / Reiss, K. / Ferreiros, N. / Geisslinger, G. / Batista, V.S. / Ji, X. / Cinatl Jr., J. / Keppler, O.T. / Xiong, Y.
History
DepositionJun 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 10, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2018Group: Data collection / Database references / Structure summary
Category: citation / citation_author / entity
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _entity.formula_weight
Revision 1.2Nov 7, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_value_order / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)261,85163
Polymers253,7064
Non-polymers8,14659
Water4,936274
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area30000 Å2
ΔGint-339 kcal/mol
Surface area69240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.691, 146.671, 99.131
Angle α, β, γ (deg.)90.00, 114.53, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: TRP / End label comp-ID: TRP / Refine code: _ / Auth seq-ID: 113 - 598 / Label seq-ID: 37 - 522

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Protein , 1 types, 4 molecules ABCD

#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


Mass: 63426.375 Da / Num. of mol.: 4 / Mutation: H206R, D207N
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

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Non-polymers , 9 types, 333 molecules

#2: Chemical
ChemComp-HFD / 2-fluoro-9-{5-O-[(R)-hydroxy{[(R)-hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl]-beta-D-arabinofuranosyl}-9H-purin-6-a mine / Fludarabine-TRIPHOSPHATE


Mass: 525.171 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15FN5O13P3
#3: Chemical
ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#4: Chemical
ChemComp-DTP / 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE


Mass: 491.182 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H16N5O12P3
#5: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Mg
#6: Chemical...
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 23 / Source method: obtained synthetically / Formula: Na
#7: Chemical
ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H5NO2
#8: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#9: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 274 / Source method: isolated from a natural source / Formula: H2O

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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: 2.29 Å3/Da / Density % sol: 46.19 %
Crystal growTemperature: 298 K / Method: microbatch / Details: 100 MM BIS-TRIS PH 6.7 AND 25% (W/V) PEG1500

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 100587 / % possible obs: 99.5 % / Redundancy: 5.7 % / CC1/2: 0.983 / Rmerge(I) obs: 0.158 / Net I/σ(I): 9.3
Reflection shellResolution: 2.3→2.34 Å / Redundancy: 5.6 % / Num. unique obs: 5041 / CC1/2: 0.185 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 2.3→50 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.932 / SU B: 14.373 / SU ML: 0.162 / Cross valid method: THROUGHOUT / ESU R: 0.308 / ESU R Free: 0.207 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21213 5169 5.1 %RANDOM
Rwork0.17631 ---
obs0.17817 95366 96.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 45.175 Å2
Baniso -1Baniso -2Baniso -3
1-2 Å20 Å2-0.02 Å2
2---1.11 Å20 Å2
3----0.62 Å2
Refinement stepCycle: 1 / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15649 0 489 274 16412
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.01916517
X-RAY DIFFRACTIONr_bond_other_d0.0030.0215165
X-RAY DIFFRACTIONr_angle_refined_deg2.2251.98822376
X-RAY DIFFRACTIONr_angle_other_deg1.111335241
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.66251914
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.94523.931809
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.61152913
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.50715112
X-RAY DIFFRACTIONr_chiral_restr0.1210.22349
X-RAY DIFFRACTIONr_gen_planes_refined0.010.02117900
X-RAY DIFFRACTIONr_gen_planes_other0.0030.023380
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.7012.4167694
X-RAY DIFFRACTIONr_mcbond_other1.6982.4147691
X-RAY DIFFRACTIONr_mcangle_it2.7513.5979582
X-RAY DIFFRACTIONr_mcangle_other2.7513.5989583
X-RAY DIFFRACTIONr_scbond_it2.5272.7258823
X-RAY DIFFRACTIONr_scbond_other2.5072.728819
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.9783.97112785
X-RAY DIFFRACTIONr_long_range_B_refined7.27445.25568360
X-RAY DIFFRACTIONr_long_range_B_other7.27445.25468360
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A317780.08
12B317780.08
21A316000.09
22C316000.09
31A317380.08
32D317380.08
41B315720.08
42C315720.08
51B317280.08
52D317280.08
61C317040.08
62D317040.08
LS refinement shellResolution: 2.275→2.334 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 219 -
Rwork0.262 4139 -
obs--56.6 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.75470.3007-0.121.76320.07370.75080.0695-0.1839-0.05660.3352-0.0298-0.2380.05010.1719-0.03970.0663-0.0014-0.04970.07290.00170.054233.4399-4.46855.3574
20.98660.1189-0.1921.2513-0.0831.1811-0.06640.2991-0.1108-0.21910.07160.29730.2325-0.4307-0.00530.0928-0.1193-0.04350.2606-0.03940.13364.9046-16.5649-34.5516
30.83740.26850.16781.14520.06751.4127-0.04360.2440.036-0.17670.0559-0.3081-0.02280.2351-0.01240.0335-0.02570.05110.13290.00630.101937.6734-1.6496-33.7036
40.97540.02770.11991.2331-0.04291.39440.0205-0.02760.16810.14770.00660.4491-0.042-0.5285-0.02710.02260.01130.06870.2052-0.0030.2262-0.89253.8252-1.3752
50.77680.1057-0.36190.9614-0.36121.4612-0.03330.0127-0.02360.17120.00290.01040.01910.01490.03030.1233-0.0165-0.00520.1148-0.01640.283921.0483-3.1547-12.175
60.79850.25571.9891.78221.50785.4011-0.19350.2369-0.0591-0.09940.23780.1883-0.49190.6666-0.04430.092-0.1141-0.0050.14960.01980.034418.0457-4.475-7.9695
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1D113 - 598
2X-RAY DIFFRACTION1A705 - 706
3X-RAY DIFFRACTION1B703
4X-RAY DIFFRACTION1D703
5X-RAY DIFFRACTION2C114 - 598
6X-RAY DIFFRACTION2A703 - 704
7X-RAY DIFFRACTION2C704 - 705
8X-RAY DIFFRACTION3B114 - 598
9X-RAY DIFFRACTION3B701 - 702
10X-RAY DIFFRACTION3C703
11X-RAY DIFFRACTION3D702
12X-RAY DIFFRACTION4A114 - 598
13X-RAY DIFFRACTION4A701 - 702
14X-RAY DIFFRACTION4C702
15X-RAY DIFFRACTION4D701
16X-RAY DIFFRACTION5A707 - 713
17X-RAY DIFFRACTION5B704 - 709
18X-RAY DIFFRACTION5D704 - 709
19X-RAY DIFFRACTION6A822
20X-RAY DIFFRACTION6B805
21X-RAY DIFFRACTION6D830 - 850

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