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

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Basic information

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


Defective HPRT1 disrupts guanine and hypoxanthine salvage / GMP catabolic process / adenine metabolic process / cerebral cortex neuron differentiation / positive regulation of dopamine metabolic process / hypoxanthine salvage / hypoxanthine phosphoribosyltransferase / lymphocyte proliferation / IMP metabolic process / guanine phosphoribosyltransferase activity ...Defective HPRT1 disrupts guanine and hypoxanthine salvage / GMP catabolic process / adenine metabolic process / cerebral cortex neuron differentiation / positive regulation of dopamine metabolic process / hypoxanthine salvage / hypoxanthine phosphoribosyltransferase / lymphocyte proliferation / IMP metabolic process / guanine phosphoribosyltransferase activity / guanine salvage / hypoxanthine metabolic process / hypoxanthine phosphoribosyltransferase activity / Purine salvage / grooming behavior / GMP salvage / 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 / cytosol / cytoplasm
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: 2.27 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 5, 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

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)100,23716
Polymers98,0654
Non-polymers2,17212
Water2,918162
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11910 Å2
ΔGint-98 kcal/mol
Surface area30120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.636, 129.595, 64.325
Angle α, β, γ (deg.)90.000, 103.800, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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-JEI / (3-{(2S,4R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-[(2-phosphonoethoxy)methyl]pyrrolidin-1-yl}-3-oxopropyl)phosphonic acid


Mass: 494.333 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H24N6O9P2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / 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: 2.44 Å3/Da / Density % sol: 49.55 %
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: Jun 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95373 Å / Relative weight: 1
ReflectionResolution: 2.22→43.98 Å / Num. obs: 42442 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Redundancy: 2 % / Biso Wilson estimate: 36.36 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.045 / Rpim(I) all: 0.0448 / Net I/σ(I): 9.5
Reflection shellResolution: 2.22→2.405 Å / Redundancy: 2.5 % / Mean I/σ(I) obs: 1.8 / Num. unique obs: 9236 / CC1/2: 0.5 / % possible all: 96.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.27→43.98 Å / SU ML: 0.2892 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.5068
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.237 1859 4.62 %
Rwork0.1721 38356 -
obs0.175 40215 98.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 44.88 Å2
Refinement stepCycle: LAST / Resolution: 2.27→43.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6492 0 136 162 6790
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00896887
X-RAY DIFFRACTIONf_angle_d1.03289372
X-RAY DIFFRACTIONf_chiral_restr0.05821061
X-RAY DIFFRACTIONf_plane_restr0.00891184
X-RAY DIFFRACTIONf_dihedral_angle_d7.7384976
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.27-2.330.34581340.29892742X-RAY DIFFRACTION91.94
2.33-2.40.31491430.25572977X-RAY DIFFRACTION98.67
2.4-2.480.29541430.22762934X-RAY DIFFRACTION99.16
2.48-2.570.311430.20372957X-RAY DIFFRACTION99.04
2.57-2.670.271460.18952989X-RAY DIFFRACTION99.4
2.67-2.790.25631420.18862950X-RAY DIFFRACTION99.36
2.79-2.940.29381460.18613004X-RAY DIFFRACTION99.43
2.94-3.120.27251420.1872941X-RAY DIFFRACTION99.45
3.12-3.360.23751460.18043008X-RAY DIFFRACTION99.68
3.36-3.70.2511420.18012910X-RAY DIFFRACTION97.38
3.7-4.240.20641420.13962944X-RAY DIFFRACTION98.34
4.24-5.330.18841450.13093003X-RAY DIFFRACTION99.56
5.33-43.980.1871450.15442997X-RAY DIFFRACTION98.5

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