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

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Basic information

Entry
Database: PDB / ID: 4raq
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-phosphonomethoxyethyl)-2-aminoethyl]hypoxanthine / 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 salvage / hypoxanthine metabolic process / cerebral cortex neuron differentiation / positive regulation of dopamine metabolic process / hypoxanthine phosphoribosyltransferase / lymphocyte proliferation ...adenine metabolic process / Defective HPRT1 disrupts guanine and hypoxanthine salvage / GMP catabolic process / guanine salvage / hypoxanthine salvage / hypoxanthine metabolic process / cerebral cortex neuron differentiation / positive regulation of dopamine metabolic process / hypoxanthine phosphoribosyltransferase / lymphocyte proliferation / guanine phosphoribosyltransferase activity / IMP metabolic process / GMP salvage / hypoxanthine phosphoribosyltransferase activity / grooming behavior / Purine salvage / 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-3L8 / Hypoxanthine-guanine phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 Å
AuthorsKeough, D.T. / Hockova, 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)99,82016
Polymers97,9254
Non-polymers1,89612
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11250 Å2
ΔGint-95 kcal/mol
Surface area29040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.328, 92.605, 115.013
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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-3L8 / [(2-{[2-(6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl](2-phosphonoethyl)amino}ethoxy)methyl]phosphonic acid


Mass: 425.271 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H21N5O8P2
#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.: 123 / 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: 2.08 Å3/Da / Density % sol: 40.74 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2 M calcium acetate, 0.1 M Tris-HCl, pH 7.5, 20% PEG3000, VAPOR DIFFUSION, HANGING DROP

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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: Aug 5, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95369 Å / Relative weight: 1
ReflectionResolution: 2.53→92.61 Å / Num. obs: 27294 / % 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: 1.8.2_1309)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.53→58.9 Å / SU ML: 0.4 / σ(F): 1.33 / Phase error: 30.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2691 1999 7.34 %Random
Rwork0.1775 ---
obs0.1844 27220 97.34 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.53→58.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6295 0 116 123 6534
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086528
X-RAY DIFFRACTIONf_angle_d1.1598833
X-RAY DIFFRACTIONf_dihedral_angle_d17.1322466
X-RAY DIFFRACTIONf_chiral_restr0.076991
X-RAY DIFFRACTIONf_plane_restr0.0051109
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.53-2.59120.3544980.3121244X-RAY DIFFRACTION68
2.5912-2.66130.37921390.26531732X-RAY DIFFRACTION96
2.6613-2.73960.34761430.25691818X-RAY DIFFRACTION100
2.7396-2.8280.36681440.2381833X-RAY DIFFRACTION100
2.828-2.92910.31941450.22021820X-RAY DIFFRACTION100
2.9291-3.04640.32921440.21551814X-RAY DIFFRACTION100
3.0464-3.1850.33951460.20521844X-RAY DIFFRACTION100
3.185-3.35290.29731450.19971832X-RAY DIFFRACTION100
3.3529-3.5630.25561460.17171835X-RAY DIFFRACTION100
3.563-3.8380.23681470.15341857X-RAY DIFFRACTION100
3.838-4.22420.23511470.13761846X-RAY DIFFRACTION100
4.2242-4.83520.23431480.12191880X-RAY DIFFRACTION100
4.8352-6.09080.19951500.15491885X-RAY DIFFRACTION100
6.0908-58.91550.26621570.18581981X-RAY DIFFRACTION99
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)
13.2318-3.4516-0.80185.6049-1.85667.50180.2258-0.00230.5481-0.6395-0.0146-0.7991-0.91840.7812-0.25710.4278-0.12440.10720.46990.01390.713357.68197.8279-12.253
21.82050.6669-0.72514.1986-1.76476.53740.0720.1739-0.3906-0.04050.162-0.2740.5007-0.3443-0.22680.34650.0193-0.03080.383-0.00920.489846.4841-12.4131-3.3198
35.11662.4694-2.30276.4988-4.05994.15030.0291-0.68960.1654-0.0772-0.21170.02440.39680.44120.20650.42940.0889-0.02270.521-0.0690.378459.5003-17.1231.4764
47.2082-3.7008-0.54339.9417-7.63498.0608-0.5751-0.6469-0.12790.3425-0.4334-1.43570.31251.15941.04650.79390.25250.07930.67160.03240.760465.3451-12.351-9.464
51.4651-2.37770.40644.63951.65347.7123-0.1229-0.28030.62570.33610.2116-0.6566-0.23650.86340.02220.4283-0.1457-0.03350.4623-0.06880.675962.1985.6419-3.3119
64.44371.5227-0.098.58911.17664.37910.12770.37910.0152-0.59680.0074-0.6447-0.07410.3286-0.17030.44150.07650.08410.45560.04520.435945.9193.6098-20.905
75.81221.19034.25570.7367-0.36517.92650.1125-0.02310.465-0.0852-0.17280.2-0.7754-0.44740.05680.60430.120.12870.49850.0270.434432.221713.8531-15.4197
85.8539-3.06120.82345.9636-5.17835.6337-1.01130.04440.16690.53270.5542-0.3168-0.8355-0.05920.54640.6669-0.05310.03220.46520.06780.543929.598617.1361-13.6613
99.3305-3.38910.29548.69111.36693.64560.18450.25070.7303-0.4221-0.2170.2923-0.32310.05020.03180.64270.06230.13270.42230.07090.466431.357920.4964-27.3103
104.0788-1.6114-3.97193.44581.99589.59050.38410.7273-0.1067-0.6198-0.7861-0.0139-0.48780.02870.43980.6680.08770.21250.56990.08060.626943.801717.8087-31.1784
112.81213.59820.30419.25710.63383.7569-0.1040.7321-0.3332-1.0131-0.0984-0.15780.3021-0.33570.19320.63790.1430.07780.6448-0.01580.41839.323-1.1109-30.7928
122.95410.99110.47167.46092.00263.4252-0.0402-0.32060.21060.21580.07320.4264-0.0817-0.5408-0.00860.3120.0760.01460.51750.04730.291530.2429-3.20857.2877
135.9058-0.26351.8776.8117-4.99937.59220.0319-0.39290.61890.4833-0.2486-0.3975-0.83110.07960.2380.52990.0194-0.03290.5122-0.09990.412848.32195.60887.1283
146.74642.75430.75796.66470.00596.98240.0681-0.57740.05340.79910.0476-0.8513-0.61240.533-0.12570.5684-0.0527-0.11970.4673-0.0840.431449.20782.940520.2844
152.90660.16432.24887.17121.31646.06740.1023-0.5836-0.14850.48940.0280.21010.0586-0.1308-0.07870.39360.02260.02840.49840.01710.301234.8016-9.606915.0766
168.80011.1941-1.4964.2982-1.13823.29480.2044-0.8719-0.03320.3702-0.38830.07610.6489-0.14030.27590.6611-0.0960.01810.6270.07210.446116.2476-0.72853.6573
176.7878-0.87994.22287.0897-3.13477.3041-0.6842-0.63920.69730.18290.30970.3137-1.2101-0.79190.32970.60490.1266-0.00730.4757-0.12940.452924.551814.05473.4234
183.52620.69522.54834.83534.77779.19640.3034-0.4932-0.33360.0374-0.1511-0.52220.3286-0.7079-0.08630.3694-0.10530.01370.45760.04180.366725.5199-7.8961-8.4774
195.741-3.6710.40397.1721-3.48212.12150.41010.07010.1738-0.2278-0.1278-0.2021-0.02740.0713-0.21660.45210.02430.01310.5501-0.0060.304426.2739-2.4049-17.4511
207.774-3.46860.07154.0340.22575.9062-0.03490.7881-0.0805-0.15160.0050.11590.19560.06140.01390.4099-0.04360.05370.60030.03260.307321.2416-2.4145-21.9939
212.5294-0.9151-2.65549.6876.21019.1740.18960.51220.24750.67540.04840.36821.7532-0.7189-0.30940.46110.0628-0.03440.87070.11630.44819.0938-0.9968-23.7099
224.99661.7983-0.64367.57425.02348.38310.1421-0.4702-0.1391-0.1019-0.25220.8136-0.2036-1.19040.15630.4550.0376-0.05640.73320.0810.396211.5145-4.0815-12.5613
234.47921.1622-1.16717.13021.15693.9171-0.26820.640.33770.30590.45430.2037-0.9446-1.0305-0.18490.60010.15920.09190.85470.00930.357516.06549.7779-5.342
243.45513.2279-0.10468.37972.51955.88560.491-0.53340.89640.3645-0.3191-0.2493-1.9949-0.4914-0.24030.72870.10190.08920.4525-0.07020.409622.113212.6623-3.3657
253.54074.90840.11329.78373.07182.8643-1.1499-2.45461.34731.47790.83351.8841-0.7186-2.98130.26631.04410.44590.26321.46590.08321.096213.513622.1843-2.3955
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 4 through 37 )
2X-RAY DIFFRACTION2chain 'A' and (resid 38 through 100 )
3X-RAY DIFFRACTION3chain 'A' and (resid 101 through 165 )
4X-RAY DIFFRACTION4chain 'A' and (resid 166 through 179 )
5X-RAY DIFFRACTION5chain 'A' and (resid 180 through 217 )
6X-RAY DIFFRACTION6chain 'B' and (resid 4 through 56 )
7X-RAY DIFFRACTION7chain 'B' and (resid 57 through 85 )
8X-RAY DIFFRACTION8chain 'B' and (resid 86 through 102 )
9X-RAY DIFFRACTION9chain 'B' and (resid 113 through 165 )
10X-RAY DIFFRACTION10chain 'B' and (resid 166 through 179 )
11X-RAY DIFFRACTION11chain 'B' and (resid 180 through 217 )
12X-RAY DIFFRACTION12chain 'C' and (resid 5 through 55 )
13X-RAY DIFFRACTION13chain 'C' and (resid 56 through 100 )
14X-RAY DIFFRACTION14chain 'C' and (resid 101 through 165 )
15X-RAY DIFFRACTION15chain 'C' and (resid 166 through 217 )
16X-RAY DIFFRACTION16chain 'D' and (resid 3 through 17 )
17X-RAY DIFFRACTION17chain 'D' and (resid 18 through 37 )
18X-RAY DIFFRACTION18chain 'D' and (resid 38 through 56 )
19X-RAY DIFFRACTION19chain 'D' and (resid 57 through 85 )
20X-RAY DIFFRACTION20chain 'D' and (resid 86 through 139 )
21X-RAY DIFFRACTION21chain 'D' and (resid 140 through 152 )
22X-RAY DIFFRACTION22chain 'D' and (resid 153 through 179 )
23X-RAY DIFFRACTION23chain 'D' and (resid 180 through 197 )
24X-RAY DIFFRACTION24chain 'D' and (resid 198 through 208 )
25X-RAY DIFFRACTION25chain 'D' and (resid 209 through 217 )

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