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- PDB-5hia: Human hypoxanthine-guanine phosphoribosyltransferase in complex w... -

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Basic information

Entry
Database: PDB / ID: 5hia
TitleHuman hypoxanthine-guanine phosphoribosyltransferase in complex with [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine
ComponentsHypoxanthine-guanine phosphoribosyltransferase
KeywordsTRANSFERASE / purine salvage / malaria / nuceloside phosphonate / enzyme / inhibitor
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 / purine ribonucleoside salvage / Azathioprine ADME / 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. / Rossmann fold - #2020 / Phosphoribosyl transferase domain / Phosphoribosyltransferase-like / Phosphoribosyltransferase domain / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-YPG / Hypoxanthine-guanine phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.773 Å
AuthorsGuddat, L.W. / Keough, D.T. / Rejman, D.
CitationJournal: ACS Chem. Biol. / Year: 2017
Title: Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics.
Authors: Keough, D.T. / Rejman, D. / Pohl, R. / Zbornikova, E. / Hockova, D. / Croll, T. / Edstein, M.D. / Birrell, G.W. / Chavchich, M. / Naesens, L.M.J. / Pierens, G.K. / Brereton, I.M. / Guddat, L.W.
History
DepositionJan 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2017Group: Author supporting evidence / Data collection
Category: diffrn_source / pdbx_struct_assembly_auth_evidence
Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Dec 6, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Dec 13, 2017Group: Database references / Category: citation / Item: _citation.title
Revision 1.4Sep 27, 2023Group: 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_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_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

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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)103,68816
Polymers101,5094
Non-polymers2,18012
Water7,999444
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11700 Å2
ΔGint-100 kcal/mol
Surface area30380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.718, 97.606, 130.329
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Detailstetramer according to analytical ultracentrifugation

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Components

#1: Protein
Hypoxanthine-guanine phosphoribosyltransferase / HGPRTase


Mass: 25377.170 Da / Num. of mol.: 4 / Mutation: C23A,C206A
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-YPG / [3-[(3~{R},4~{R})-3-(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)-4-[(2~{S})-2-oxidanyl-2-phosphono-ethoxy]pyrrolidin-1-y l]-3-oxidanylidene-propyl]phosphonic acid / [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine


Mass: 496.306 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H22N6O10P2
#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.: 444 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.18 Å3/Da / Density % sol: 43.55 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.3 M sodium acetate, 17.5% PEG 3350 / PH range: 4.5-6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 1, 2015
RadiationMonochromator: Si(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.77→47.61 Å / Num. all: 86593 / Num. obs: 86593 / % possible obs: 99.7 % / Redundancy: 7.23 % / Rmerge(I) obs: 0.099 / Net I/σ(I): 11.6
Reflection shellResolution: 1.77→1.81 Å / Redundancy: 6.92 % / Rmerge(I) obs: 0.892 / % possible all: 95.8

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GEP

3gep


Resolution: 1.773→47.607 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.17 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2315 1998 2.31 %
Rwork0.2066 --
obs0.2072 86441 99.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.773→47.607 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6478 0 136 444 7058
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077048
X-RAY DIFFRACTIONf_angle_d1.1329622
X-RAY DIFFRACTIONf_dihedral_angle_d15.5042814
X-RAY DIFFRACTIONf_chiral_restr0.0421082
X-RAY DIFFRACTIONf_plane_restr0.0051217
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.773-1.81740.29721360.2775770X-RAY DIFFRACTION97
1.8174-1.86650.27791420.25255974X-RAY DIFFRACTION100
1.8665-1.92140.46561400.40015928X-RAY DIFFRACTION99
1.9214-1.98340.34991410.30095990X-RAY DIFFRACTION100
1.9834-2.05430.25371430.22086007X-RAY DIFFRACTION100
2.0543-2.13660.25531420.21116007X-RAY DIFFRACTION100
2.1366-2.23380.24641410.2355969X-RAY DIFFRACTION100
2.2338-2.35160.36851420.30796032X-RAY DIFFRACTION100
2.3516-2.49890.23351430.20466056X-RAY DIFFRACTION100
2.4989-2.69180.24491430.19536019X-RAY DIFFRACTION100
2.6918-2.96270.20031440.19696085X-RAY DIFFRACTION100
2.9627-3.39130.21431440.18776069X-RAY DIFFRACTION100
3.3913-4.27230.15691460.16046161X-RAY DIFFRACTION100
4.2723-47.62380.17971510.15116376X-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)
12.9076-0.9311-0.48470.95480.15592.3120.12070.23510.0777-0.0668-0.1938-0.1935-0.45670.50310.00730.1962-0.09220.00920.44640.01710.202333.9897-8.5084-38.3359
21.68450.863-0.12261.28120.13681.77420.0461-0.0584-0.18750.0483-0.0539-0.01280.25010.09840.00570.17770.0436-0.01940.33160.02880.226627.7817-25.9013-26.5763
35.27551.799-0.89687.2038-1.96720.5717-0.0313-0.3547-0.5019-0.23950.0291-0.43070.18220.3301-0.01020.21370.10980.04470.44510.03740.244228.9677-26.8275-16.3693
41.0836-0.31540.13650.7085-0.09771.47180.0064-0.199-0.00290.0583-0.0509-0.0838-0.06530.52130.03040.1366-0.0127-0.00660.46570.01220.202239.1685-16.557-23.9764
52.5661.05310.40673.3392-1.3211.74090.00640.0031-0.2682-0.0052-0.0728-0.42980.14180.43170.120.14490.02340.02860.3635-0.03730.251230.1959-23.0873-48.5577
63.4728-0.92820.08532.35030.23232.9607-0.0013-0.09530.10220.1330.0198-0.1268-0.19270.0482-0.00460.111-0.00840.03740.11780.0150.114113.0299-8.3282-46.9214
73.986-0.5275-0.29392.9260.87784.7608-0.0564-0.3896-0.19570.2224-0.11730.08460.0455-0.27740.04740.1261-0.02350.00440.21860.02140.177610.5451-12.0464-41.6836
82.9915-0.4228-0.27842.2766-0.78092.31510.0510.0549-0.02750.15490.02110.13530.02840.0672-0.07710.0659-0.005500.16980.03010.15281.2062-9.7049-52.6474
92.6587-0.4775-0.39821.58250.01382.299-0.0412-0.09490.01150.15710.1395-0.1115-0.01430.125-0.05810.0212-0.02110.01150.05170.01310.056413.895-8.042-60.3177
102.13890.81530.23675.470.02891.4846-0.03710.2175-0.3284-0.35880.1664-0.15750.20120.1374-0.13270.15180.02950.01310.2691-0.03490.205123.5725-26.7422-55.5486
114.2351-2.5585-2.36552.38132.19634.08150.11780.1678-0.30910.3951-0.48480.2510.283-0.77540.36780.1161-0.06720.00660.346-0.02630.1809-1.5017-22.4091-15.52
123.6547-0.50360.19997.3190.26176.19110.1582-0.5227-0.81480.36580.07140.10780.8155-0.2362-0.1790.2609-0.0525-0.06140.2890.12120.41028.6838-33.6635-19.5065
130.83780.6190.75281.5116-0.13231.8112-0.04980.1021-0.0344-0.07660.03180.0096-0.06550.14980.01670.1397-0.00820.01030.23080.00630.1715.6144-8.7541-21.2082
142.09681.0613-0.82011.51140.6221.4287-0.0056-0.0845-0.069-0.0950.0855-0.05220.1030.1519-0.0760.0880.0221-0.01340.1731-0.01560.097222.3932-5.5993-13.0353
151.0291.04340.78612.70060.52531.1394-0.0436-0.0726-0.1172-0.05530.11480.34370.1782-0.34870.01880.05450.03080.04370.1823-0.01930.014413.2602-6.858-5.4528
163.9775-2.83590.48816.1057-0.71654.0959-0.0353-0.604-0.33710.18890.08920.08260.22270.20950.00270.156-0.0236-0.02370.24020.05460.13811.9489-24.7472-10.2617
172.7562-0.57460.32435.7458-0.10892.84020.1557-0.6353-0.85330.47050.26110.27930.4442-0.2026-0.41130.2829-0.0084-0.06210.34340.16440.35113.3556-32.8038-11.4499
181.47361.49230.04161.5016-0.03312.64690.026-0.08080.07550.12340.0590.2462-0.2391-0.5201-0.0840.14060.07240.02330.33870.0160.1979-4.6107-14.5581-28.307
190.9976-0.6694-0.7343.1130.71343.4744-0.0342-0.0759-0.22710.14220.1063-0.11150.40410.1075-0.08030.1104-0.0139-0.02410.20990.00640.24916.9648-31.8386-39.428
202.1709-1.90791.9983.3784-0.04194.19980.13010.30850.0361-0.1199-0.0999-0.22560.14170.6675-0.00980.16440.02310.02370.30470.00790.222711.4964-27.1994-40.7483
212.95270.7562-0.69035.49280.56584.2288-0.1556-0.4175-0.20220.35630.0175-0.08480.15050.11350.17510.2118-0.03950.03180.3017-0.01460.19468.4905-31.122-48.8052
225.2225-3.15364.60313.5436-2.8255.4214-0.05330.0191-0.4011-0.12390.2120.42560.0164-0.2529-0.030.2069-0.05870.01740.2335-0.03170.2431-2.302-31.9155-58.4574
232.2347-0.0085-0.09771.48050.38452.73030.01550.0179-0.3053-0.04610.01310.12120.4003-0.45830.01560.1776-0.067-0.02030.20190.00130.2518-5.2607-34.7474-44.8574
242.2503-0.65020.63033.1045-1.39232.0967-0.05890.0474-0.0422-0.06330.14920.13640.1073-0.5326-0.16730.08020.0096-0.00990.20060.01550.1387-7.4606-18.5262-38.4824
251.3353-1.258-0.45923.2302-0.52040.6042-0.0454-0.13330.03270.13170.21520.1575-0.2249-0.6652-0.02350.12350.09160.02230.26410.02980.1915-7.9375-10.4436-38.066
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 37 )
2X-RAY DIFFRACTION2chain 'A' and (resid 38 through 86 )
3X-RAY DIFFRACTION3chain 'A' and (resid 87 through 121 )
4X-RAY DIFFRACTION4chain 'A' and (resid 122 through 217 )
5X-RAY DIFFRACTION5chain 'B' and (resid 3 through 37 )
6X-RAY DIFFRACTION6chain 'B' and (resid 38 through 70 )
7X-RAY DIFFRACTION7chain 'B' and (resid 71 through 87 )
8X-RAY DIFFRACTION8chain 'B' and (resid 88 through 127 )
9X-RAY DIFFRACTION9chain 'B' and (resid 128 through 179 )
10X-RAY DIFFRACTION10chain 'B' and (resid 180 through 217 )
11X-RAY DIFFRACTION11chain 'C' and (resid 4 through 17 )
12X-RAY DIFFRACTION12chain 'C' and (resid 18 through 37 )
13X-RAY DIFFRACTION13chain 'C' and (resid 38 through 85 )
14X-RAY DIFFRACTION14chain 'C' and (resid 86 through 139 )
15X-RAY DIFFRACTION15chain 'C' and (resid 140 through 179 )
16X-RAY DIFFRACTION16chain 'C' and (resid 180 through 197 )
17X-RAY DIFFRACTION17chain 'C' and (resid 198 through 217 )
18X-RAY DIFFRACTION18chain 'D' and (resid 4 through 37 )
19X-RAY DIFFRACTION19chain 'D' and (resid 38 through 70 )
20X-RAY DIFFRACTION20chain 'D' and (resid 71 through 86 )
21X-RAY DIFFRACTION21chain 'D' and (resid 87 through 103 )
22X-RAY DIFFRACTION22chain 'D' and (resid 104 through 127 )
23X-RAY DIFFRACTION23chain 'D' and (resid 128 through 179 )
24X-RAY DIFFRACTION24chain 'D' and (resid 180 through 197 )
25X-RAY DIFFRACTION25chain 'D' and (resid 198 through 217 )

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