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- PDB-8ts4: Crystal structure of T. Brucei hypoxanthine guanine phosphoribosy... -

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Basic information

Entry
Database: PDB / ID: 8ts4
TitleCrystal structure of T. Brucei hypoxanthine guanine phosphoribosyltransferase in complex with [2S,4S]-4-Guanin-9-yl-2-(2-phosphonoethoxymethyl)-1-N-(3-phosphonopropionyl)pyrrolidine
ComponentsHypoxanthine-guanine phosphoribosyltransferase
KeywordsTRANSFERASE / Inhibitor / complex / purine base / product analog
Function / homology
Function and homology information


hypoxanthine phosphoribosyltransferase / guanine phosphoribosyltransferase activity / hypoxanthine phosphoribosyltransferase activity / IMP salvage / nuclear lumen / glycosome / ciliary plasm / purine ribonucleoside salvage / nucleotide binding / metal ion binding ...hypoxanthine phosphoribosyltransferase / guanine phosphoribosyltransferase activity / hypoxanthine phosphoribosyltransferase activity / IMP salvage / nuclear lumen / glycosome / ciliary plasm / purine ribonucleoside salvage / nucleotide binding / metal ion 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 speciesTrypanosoma brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsGuddat, L.W. / Guddat, 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 10, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,8236
Polymers46,7862
Non-polymers1,0374
Water4,828268
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization, DIMER
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3170 Å2
ΔGint-30 kcal/mol
Surface area15320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.031, 93.031, 105.701
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number94
Space group name H-MP42212
Space group name HallP4n2n
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/2
#3: y+1/2,-x+1/2,z+1/2
#4: x+1/2,-y+1/2,-z+1/2
#5: -x+1/2,y+1/2,-z+1/2
#6: -x,-y,z
#7: y,x,-z
#8: -y,-x,-z
Components on special symmetry positions
IDModelComponents
11A-529-

HOH

21B-466-

HOH

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Components

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


Mass: 23392.893 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma brucei (eukaryote) / Gene: HGPRT / Production host: Escherichia coli (E. coli)
References: UniProt: Q07010, hypoxanthine phosphoribosyltransferase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-KFF / (3-{(2S,4S)-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.: 2 / Source method: obtained synthetically / Formula: C15H24N6O9P2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 268 / 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: 49.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.2 M MgCl2 , 0.1 M Bis-Tris, pH 5.0, 20% 3350 / PH range: 5

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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 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95373 Å / Relative weight: 1
ReflectionResolution: 2.19651→45.9529 Å / Num. obs: 24294 / % possible obs: 99.92 % / Redundancy: 4 % / Biso Wilson estimate: 27.83 Å2 / CC1/2: 0.99 / Net I/σ(I): 18.4
Reflection shellResolution: 2.2→2.25 Å / Mean I/σ(I) obs: 3.5 / Num. unique obs: 1680 / CC1/2: 0.99

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→45.95 Å / SU ML: 0.2056 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 20.8364
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2217 2000 8.23 %
Rwork0.1708 22294 -
obs0.175 24294 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.48 Å2
Refinement stepCycle: LAST / Resolution: 2.2→45.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2774 0 66 268 3108
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00862905
X-RAY DIFFRACTIONf_angle_d1.02513954
X-RAY DIFFRACTIONf_chiral_restr0.0572461
X-RAY DIFFRACTIONf_plane_restr0.0116491
X-RAY DIFFRACTIONf_dihedral_angle_d17.03191081
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.250.25151380.18131542X-RAY DIFFRACTION99.29
2.25-2.310.2621420.17331581X-RAY DIFFRACTION100
2.31-2.380.23981390.17571557X-RAY DIFFRACTION100
2.38-2.460.24931400.17841556X-RAY DIFFRACTION100
2.46-2.540.23791410.16841565X-RAY DIFFRACTION100
2.55-2.650.19991410.17211578X-RAY DIFFRACTION100
2.65-2.770.2481410.17641565X-RAY DIFFRACTION100
2.77-2.910.24631410.16511576X-RAY DIFFRACTION100
2.91-3.10.23461420.18531585X-RAY DIFFRACTION100
3.1-3.330.24671430.1861590X-RAY DIFFRACTION99.94
3.33-3.670.21551430.16831599X-RAY DIFFRACTION100
3.67-4.20.21021450.1551614X-RAY DIFFRACTION100
4.2-5.290.16751480.14711637X-RAY DIFFRACTION99.94
5.29-45.950.23051560.18911749X-RAY DIFFRACTION100
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)
17.726369064560.595351740113-0.3048281845755.362025427094.799037840084.375208959210.1182214531791.001789544191.06250830412-0.872870083764-0.02901809939910.459261696102-1.51909468474-0.6456866721140.03531014746640.3403569104150.124689914280.03888581348760.5292118514390.2168246452570.5930264067929.28651471334.8794092101419.0407355994
22.540233698380.0752966898681-0.4921944861452.63457513951-0.4440370287854.293830934820.221490705672-0.2361775321690.2910459603520.334131867308-0.09466277330740.215620246339-0.0920580316066-0.120943285956-0.1296773164240.14896626123-0.05873127811370.04670778639410.188179837348-0.02040013047350.20422829177220.4758730358-7.3601461825140.4941390903
33.096789157543.097879443410.2617807144445.012905041-2.502426521427.93867465140.289479221335-0.0381375957174-0.4098402557350.116547687769-0.12086106126-0.1234804862160.5143785537650.405069274224-0.2246871496890.1789962616950.02743564647530.01540022648350.169456826928-0.03132572310750.22575508994115.8593498644-17.490791811338.8833970381
43.7907678349-2.907689993925.307748260365.71655494994-3.302048158817.826143764430.580580761502-0.00613305501552-0.8500338648550.0513943034042-0.05551021996810.5247829506960.89345870196-0.526412208148-0.3886941981670.218139653645-0.07863228164920.01172146702820.269710643141-0.03600910119970.30285444941711.2498293047-24.050430757637.9626028985
55.577103061710.4656984943340.8996021002782.003526453780.07823061472962.557847470170.0932006264663-0.0362087600520.1192652900620.21234853097-0.1098646373710.361724613130.143498591916-0.06414091456040.003611575646750.196649672383-0.05942774834290.06573549961290.2334609241130.0008652261568910.2173520116147.54312448243-14.153774290438.4605732502
60.252877116586-0.225046270731-0.4356647619242.214907948230.1126650379621.034802898630.1916855653790.8219849116560.668916531541-0.3499351098580.4028390913631.073031991760.307244920377-1.183052708110.007647758453830.228365192002-0.0750527262378-0.1304753621710.7114123062240.2808614676370.5044530156989.75122114542-5.1859680410119.2469864673
72.430306600810.6937841163040.2312536156492.17447692808-0.3552912949782.600217669190.05397612526780.2976407203710.361140090354-0.1558271022060.05599833118730.0533586696279-0.1611143459080.028690591722-0.03846322412250.140420675870.01327579440740.03870161421480.2313690438510.06512772063030.23924695360530.7728652334-2.2727911848722.8627777154
86.10774592702-0.478426010787-0.6517030863340.8725146973712.577548964747.62035365625-0.008748388811560.332865475073-0.594581484838-0.4695742090680.3274502823240.8925571924511.21722054298-0.780630013778-0.2720958063070.329879821817-0.0717331506519-0.1270239318180.3955559084660.02054186742890.33284185554825.0416666062-13.466348210815.1235342814
92.35016415407-0.143822645897-0.1474510571322.021931182750.1289915984782.636517350560.1300100719390.124234738759-0.0937396127926-0.0723977726897-0.0445279141129-0.1749720255490.1502922882920.185976363832-0.09785925603060.1187769786730.01015781860920.004266010513280.2111485130890.01698410215860.17548011859838.6683421957-11.21123341225.1476588739
103.841860316950.04673954890151.371978778674.603220219852.006596911243.747142563720.19931851565-0.155851188485-1.016875343621.136549950880.417404016222-0.7479182836540.738927137656-0.240969399831-0.5451731872540.524855452298-0.0117533570504-0.1636070731470.4937486898690.09064307852240.48211353000341.3470682322-18.66989201449.4351400844
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 3 through 16 )AA3 - 161 - 14
22chain 'A' and (resid 17 through 79 )AA17 - 7915 - 77
33chain 'A' and (resid 102 through 119 )AA102 - 11978 - 95
44chain 'A' and (resid 120 through 132 )AA120 - 13296 - 108
55chain 'A' and (resid 133 through 158 )AA133 - 158109 - 134
66chain 'A' and (resid 159 through 195 )AA159 - 195135 - 171
77chain 'B' and (resid 5 through 69 )BB5 - 691 - 65
88chain 'B' and (resid 70 through 107 )BB70 - 10766 - 84
99chain 'B' and (resid 108 through 188 )BB108 - 18885 - 165
1010chain 'B' and (resid 189 through 203 )BB189 - 203166 - 180

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