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- PDB-8tpy: Structure of human hypoxanthine guanine phosphoribzosyltransferas... -

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Basic information

Entry
Database: PDB / ID: 8tpy
TitleStructure of human hypoxanthine guanine phosphoribzosyltransferase in complex with [2S,4R] 4-Guanin-9-yl-2-hydroxymethyl-1-N-(3-phosphonopropionyl)pyrrolidine
ComponentsHypoxanthine-guanine phosphoribosyltransferase
KeywordsTRANSFERASE / inhibitor / complex / purine base
Function / homology
Function and homology information


Defective HPRT1 disrupts guanine and hypoxanthine salvage / positive regulation of dopamine metabolic process / GMP catabolic process / adenine metabolic process / cerebral cortex neuron differentiation / hypoxanthine salvage / hypoxanthine phosphoribosyltransferase / guanine phosphoribosyltransferase activity / guanine salvage / hypoxanthine metabolic process ...Defective HPRT1 disrupts guanine and hypoxanthine salvage / positive regulation of dopamine metabolic process / GMP catabolic process / adenine metabolic process / cerebral cortex neuron differentiation / hypoxanthine salvage / hypoxanthine phosphoribosyltransferase / guanine phosphoribosyltransferase activity / guanine salvage / hypoxanthine metabolic process / IMP metabolic process / hypoxanthine phosphoribosyltransferase activity / lymphocyte proliferation / Purine salvage / GMP salvage / grooming behavior / IMP salvage / striatum development / AMP salvage / dopaminergic neuron differentiation / purine nucleotide biosynthetic process / Azathioprine ADME / purine ribonucleoside salvage / dendrite morphogenesis / central nervous system neuron development / dopamine metabolic process / response to amphetamine / locomotory behavior / T cell mediated cytotoxicity / protein homotetramerization / nucleotide binding / magnesium ion binding / extracellular exosome / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Hypoxanthine phosphoribosyl transferase / : / Purine/pyrimidine phosphoribosyl transferases signature. / Phosphoribosyl transferase domain / Phosphoribosyltransferase-like / Phosphoribosyltransferase domain
Similarity search - Domain/homology
: / Hypoxanthine-guanine phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsGuddat, L.W.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1147368 Australia
CitationJournal: J.Med.Chem. / Year: 2024
Title: Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design.
Authors: Keough, D.T. / Petrova, M. / King, G. / Kratochvil, M. / Pohl, R. / Dolezelova, E. / Zikova, A. / Guddat, L.W. / Rejman, D.
History
DepositionAug 6, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: 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

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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)99,70712
Polymers98,0654
Non-polymers1,6428
Water2,000111
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9250 Å2
ΔGint-68 kcal/mol
Surface area30990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.461, 93.420, 129.320
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
Hypoxanthine-guanine phosphoribosyltransferase / HGPRT / HGPRTase


Mass: 24516.217 Da / Num. of mol.: 4 / Mutation: C22A C105A C205A
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-JG6 / {3-[(2S,4R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-oxopropyl}phosphonic acid


Mass: 386.300 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H19N6O6P / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 2.29 Å3/Da / Density % sol: 46.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.3 M calcium acetate, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.95373 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95373 Å / Relative weight: 1
ReflectionResolution: 2.5→75.73 Å / Num. obs: 31919 / % possible obs: 100 % / Redundancy: 3.5 % / Biso Wilson estimate: 37.4 Å2 / CC1/2: 0.9 / Net I/σ(I): 7
Reflection shellResolution: 2.5→2.708 Å / Redundancy: 2 % / Num. unique obs: 6719 / CC1/2: 0.75 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→75.73 Å / SU ML: 0.2709 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.1917
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2596 1996 6.26 %
Rwork0.1998 29891 -
obs0.2036 31887 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.24 Å2
Refinement stepCycle: LAST / Resolution: 2.5→75.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6101 0 108 111 6320
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00376380
X-RAY DIFFRACTIONf_angle_d0.69278662
X-RAY DIFFRACTIONf_chiral_restr0.0462976
X-RAY DIFFRACTIONf_plane_restr0.00581094
X-RAY DIFFRACTIONf_dihedral_angle_d14.63792339
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.560.33971400.24372106X-RAY DIFFRACTION99.96
2.56-2.630.32351410.2152089X-RAY DIFFRACTION100
2.63-2.710.29881410.22112117X-RAY DIFFRACTION100
2.71-2.80.33811400.22262099X-RAY DIFFRACTION99.82
2.8-2.90.29731400.22012102X-RAY DIFFRACTION99.96
2.9-3.010.29521410.20852107X-RAY DIFFRACTION99.96
3.01-3.150.2641430.20432134X-RAY DIFFRACTION100
3.15-3.320.24881420.20992132X-RAY DIFFRACTION99.96
3.32-3.520.27561420.19732115X-RAY DIFFRACTION99.96
3.52-3.80.27791410.18942125X-RAY DIFFRACTION100
3.8-4.180.21621440.17212144X-RAY DIFFRACTION99.96
4.18-4.780.18051440.16332156X-RAY DIFFRACTION100
4.78-6.020.25431460.20472175X-RAY DIFFRACTION100
6.02-75.730.27861510.22442290X-RAY DIFFRACTION99.11

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