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- PDB-4rab: Aza-acyclic nucleoside phosphonates containing a second phosphona... -

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Basic information

Entry
Database: PDB / ID: 4rab
TitleAza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their pro-drugs as antimalarial agents
ComponentsHypoxanthine-guanine phosphoribosyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Hypoxanthine-guanine phosphoribosyltransferase / Acyclic nucleoside monophosphonates / Malaria / 6-oxopurine phosphoribosyltransferase / 9-[(N-Phosphonoethyl-N-phosphonoethoxyethyl)-2-aminoethyl]-8-bromoguanine / cytoplasmic / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


adenine metabolic process / Defective HPRT1 disrupts guanine and hypoxanthine salvage / GMP catabolic process / guanine salvage / hypoxanthine metabolic process / hypoxanthine salvage / cerebral cortex neuron differentiation / positive regulation of dopamine metabolic process / lymphocyte proliferation / hypoxanthine phosphoribosyltransferase ...adenine metabolic process / Defective HPRT1 disrupts guanine and hypoxanthine salvage / GMP catabolic process / guanine salvage / hypoxanthine metabolic process / hypoxanthine salvage / cerebral cortex neuron differentiation / positive regulation of dopamine metabolic process / lymphocyte proliferation / hypoxanthine phosphoribosyltransferase / IMP metabolic process / GMP salvage / guanine phosphoribosyltransferase activity / hypoxanthine phosphoribosyltransferase activity / grooming behavior / IMP salvage / Purine salvage / striatum development / AMP salvage / dopaminergic neuron differentiation / purine nucleotide biosynthetic process / Azathioprine ADME / purine ribonucleoside salvage / dendrite morphogenesis / dopamine metabolic process / central nervous system neuron development / response to amphetamine / locomotory behavior / T cell mediated cytotoxicity / protein homotetramerization / nucleotide binding / magnesium ion binding / extracellular exosome / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Hypoxanthine phosphoribosyl transferase / Purine/pyrimidine phosphoribosyl transferases signature. / Rossmann fold - #2020 / Phosphoribosyl transferase domain / Phosphoribosyltransferase-like / Phosphoribosyltransferase domain / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-3L3 / PHOSPHATE ION / Hypoxanthine-guanine phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.264 Å
AuthorsKeough, D.T. / Hockov, D. / Janeba, Z. / Wang, T.-H. / Naesens, L. / Edstein, M.D. / Chavchich, M. / Guddat, L.W.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Aza-acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group As Inhibitors of the Human, Plasmodium falciparum and vivax 6-Oxopurine Phosphoribosyltransferases and Their Prodrugs ...Title: Aza-acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group As Inhibitors of the Human, Plasmodium falciparum and vivax 6-Oxopurine Phosphoribosyltransferases and Their Prodrugs As Antimalarial Agents.
Authors: Keough, D.T. / Hockova, D. / Janeba, Z. / Wang, T.H. / Naesens, L. / Edstein, M.D. / Chavchich, M. / Guddat, L.W.
History
DepositionSep 10, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 7, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 11, 2015Group: Database references
Revision 1.2Dec 23, 2015Group: Structure summary
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_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.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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hypoxanthine-guanine phosphoribosyltransferase
B: Hypoxanthine-guanine phosphoribosyltransferase
C: Hypoxanthine-guanine phosphoribosyltransferase
D: Hypoxanthine-guanine phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,56718
Polymers97,9254
Non-polymers2,64214
Water2,738152
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12560 Å2
ΔGint-131 kcal/mol
Surface area29320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.728, 128.958, 62.938
Angle α, β, γ (deg.)90.00, 103.04, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Hypoxanthine-guanine phosphoribosyltransferase / / HGPRT / HGPRTase


Mass: 24481.217 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HPRT1, HPRT / Production host: Escherichia coli (E. coli)
References: UniProt: P00492, hypoxanthine phosphoribosyltransferase
#2: Chemical
ChemComp-3L3 / [(E)-2-(2-{[2-(2-amino-8-bromo-6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl][(E)-2-phosphonoethenyl]amino}ethoxy)ethenyl]phosphonic acid


Mass: 529.177 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H19BrN6O8P2
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 152 / 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: 2.25 Å3/Da / Density % sol: 45.33 %
Crystal growMethod: vapor diffusion, hanging drop
Details: 20% PEG 3350, 0.2 M sodium acetate, VAPOR DIFFUSION, HANGING DROP
PH range: no buffer

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.95369 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: May 20, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95369 Å / Relative weight: 1
ReflectionResolution: 2.25→43 Å / Num. obs: 42845 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASESphasing
PHENIX(phenix.refine: 1.8_1069)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.264→41.53 Å / SU ML: 0.23 / σ(F): 1.34 / Phase error: 24.62 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2314 1875 4.7 %
Rwork0.2092 --
obs0.2103 39923 99.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.264→41.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6297 0 146 152 6595
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086632
X-RAY DIFFRACTIONf_angle_d0.8938997
X-RAY DIFFRACTIONf_dihedral_angle_d14.6152486
X-RAY DIFFRACTIONf_chiral_restr0.0621008
X-RAY DIFFRACTIONf_plane_restr0.0031128
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.264-2.32520.30941450.28642930X-RAY DIFFRACTION99
2.3252-2.39360.28751450.24652928X-RAY DIFFRACTION100
2.3936-2.47090.24951430.23272932X-RAY DIFFRACTION100
2.4709-2.55920.27771450.22932951X-RAY DIFFRACTION100
2.5592-2.66160.24121460.23452964X-RAY DIFFRACTION100
2.6616-2.78280.29571440.24432906X-RAY DIFFRACTION100
2.7828-2.92940.30911460.23662972X-RAY DIFFRACTION100
2.9294-3.11290.26881450.22632946X-RAY DIFFRACTION100
3.1129-3.35320.24951440.22522912X-RAY DIFFRACTION100
3.3532-3.69040.20861440.20112927X-RAY DIFFRACTION98
3.6904-4.2240.1851420.17712881X-RAY DIFFRACTION98
4.224-5.320.16941440.16572921X-RAY DIFFRACTION98
5.32-41.53680.20481420.18872878X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: 14.2612 Å / Origin y: 1.2646 Å / Origin z: 12.8014 Å
111213212223313233
T0.259 Å20.0035 Å20.0115 Å2-0.2677 Å20.0024 Å2--0.3064 Å2
L0.3776 °20.0954 °20.0336 °2-1.6954 °20.4642 °2--0.2935 °2
S-0.001 Å °-0.033 Å °-0.0116 Å °0.0099 Å °-0.0525 Å °0.1582 Å °0.0288 Å °-0.0347 Å °0.0573 Å °
Refinement TLS groupSelection details: all

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