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- PDB-7ljt: Porcine Dihydropyrimidine Dehydrogenase (DPD) soaked with 5-Ethyn... -

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Basic information

Entry
Database: PDB / ID: 7ljt
TitlePorcine Dihydropyrimidine Dehydrogenase (DPD) soaked with 5-Ethynyluracil (5EU), NADPH - 20 minutes
ComponentsDihydropyrimidine dehydrogenase [NADP(+)]
KeywordsFLAVOPROTEIN / Dihydropyrimidine dehydrogenase / DPD / dehydrogenase / 5-ethynyluracil / 5EU / inhibitor / inactivator
Function / homology
Function and homology information


dihydropyrimidine dehydrogenase (NADP+) / thymidine catabolic process / dihydropyrimidine dehydrogenase (NADP+) activity / uracil binding / beta-alanine biosynthetic process / thymine catabolic process / uracil catabolic process / FMN binding / flavin adenine dinucleotide binding / NADP binding ...dihydropyrimidine dehydrogenase (NADP+) / thymidine catabolic process / dihydropyrimidine dehydrogenase (NADP+) activity / uracil binding / beta-alanine biosynthetic process / thymine catabolic process / uracil catabolic process / FMN binding / flavin adenine dinucleotide binding / NADP binding / 4 iron, 4 sulfur cluster binding / protein homodimerization activity / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Dihydroprymidine dehydrogenase domain II / Dihydroprymidine dehydrogenase domain II, 4Fe-4S cluster / 4Fe-4S dicluster domain / Alpha-helical ferredoxin / Dihydroorotate dehydrogenase domain / Dihydroorotate dehydrogenase / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / 4Fe-4S ferredoxin, iron-sulphur binding, conserved site / 4Fe-4S ferredoxin-type iron-sulfur binding region signature. ...Dihydroprymidine dehydrogenase domain II / Dihydroprymidine dehydrogenase domain II, 4Fe-4S cluster / 4Fe-4S dicluster domain / Alpha-helical ferredoxin / Dihydroorotate dehydrogenase domain / Dihydroorotate dehydrogenase / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / 4Fe-4S ferredoxin, iron-sulphur binding, conserved site / 4Fe-4S ferredoxin-type iron-sulfur binding region signature. / 4Fe-4S ferredoxin-type iron-sulfur binding domain profile. / 4Fe-4S ferredoxin-type, iron-sulphur binding domain / FAD/NAD(P)-binding domain superfamily / Aldolase-type TIM barrel
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / FLAVIN MONONUCLEOTIDE / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / IRON/SULFUR CLUSTER / 5-ethynylpyrimidine-2,4(1H,3H)-dione / Dihydropyrimidine dehydrogenase [NADP(+)]
Similarity search - Component
Biological speciesSus scrofa (pig)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.98 Å
AuthorsButrin, A. / Forouzesh, D. / Beaupre, B. / Wawrzak, Z. / Liu, D. / Moran, G.
CitationJournal: Biochemistry / Year: 2021
Title: The Interaction of Porcine Dihydropyrimidine Dehydrogenase with the Chemotherapy Sensitizer: 5-Ethynyluracil.
Authors: Forouzesh, D.C. / Beaupre, B.A. / Butrin, A. / Wawrzak, Z. / Liu, D. / Moran, G.R.
History
DepositionJan 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2021Group: 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
Revision 1.2Oct 18, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_residues
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydropyrimidine dehydrogenase [NADP(+)]
B: Dihydropyrimidine dehydrogenase [NADP(+)]
C: Dihydropyrimidine dehydrogenase [NADP(+)]
D: Dihydropyrimidine dehydrogenase [NADP(+)]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)460,52536
Polymers446,4134
Non-polymers14,11232
Water64,1333560
1
A: Dihydropyrimidine dehydrogenase [NADP(+)]
B: Dihydropyrimidine dehydrogenase [NADP(+)]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,26318
Polymers223,2072
Non-polymers7,05616
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area33580 Å2
ΔGint-297 kcal/mol
Surface area68370 Å2
MethodPISA
2
C: Dihydropyrimidine dehydrogenase [NADP(+)]
D: Dihydropyrimidine dehydrogenase [NADP(+)]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,26318
Polymers223,2072
Non-polymers7,05616
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area33240 Å2
ΔGint-298 kcal/mol
Surface area68030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.251, 158.861, 162.100
Angle α, β, γ (deg.)90.000, 95.710, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Dihydropyrimidine dehydrogenase [NADP(+)] / DPD / Dihydrothymine dehydrogenase / Dihydrouracil dehydrogenase


Mass: 111603.344 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Sus scrofa (pig) / Gene: DPYD / Production host: Escherichia coli (E. coli)
References: UniProt: Q28943, dihydropyrimidine dehydrogenase (NADP+)

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Non-polymers , 6 types, 3592 molecules

#2: Chemical
ChemComp-SF4 / IRON/SULFUR CLUSTER / Iron–sulfur cluster


Mass: 351.640 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Fe4S4
#3: Chemical
ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE / Flavin adenine dinucleotide


Mass: 785.550 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
#4: Chemical
ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


Mass: 456.344 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H21N4O9P / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-Y3G / 5-ethynylpyrimidine-2,4(1H,3H)-dione


Mass: 136.108 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H4N2O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 3560 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.36 Å3/Da / Density % sol: 47.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: Crystals were obtained by soaking. In each case DPD was crystallized by the vapor diffusion, hanging drop method by mixing 3 uL of 39 uM DPD in 25 mM HEPES, 2 mM DTT, 10% glycerol, pH 7.5 ...Details: Crystals were obtained by soaking. In each case DPD was crystallized by the vapor diffusion, hanging drop method by mixing 3 uL of 39 uM DPD in 25 mM HEPES, 2 mM DTT, 10% glycerol, pH 7.5 with 3 uL of well solution containing 100 mM NaCl, 2 mM DTT, 18% PEG 6000, pH 4.7. The crystals were then soaked for 20 minutes in 25 mM HEPES, 100 mM NaCl, 2 mM DTT, 100 uM NADPH, 100 uM 5EU, 20% PEG 6000, 20% PEG 400, pH 7.5.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Sep 27, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.98→71.26 Å / Num. obs: 254113 / % possible obs: 88.6 % / Redundancy: 4.2 % / Biso Wilson estimate: 17.04 Å2 / CC1/2: 0.989 / Rmerge(I) obs: 0.138 / Rpim(I) all: 0.074 / Net I/σ(I): 7.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) all% possible all
1.98-2.0140.8151.6109400.6150.45577
10.84-71.264.50.05919.318000.9380.03398.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.19_4092refinement
xia2data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1H7X

1h7x


Resolution: 1.98→60.53 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 21.53 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.219 12776 5.03 %
Rwork0.183 241243 -
obs0.1848 254019 88.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 64.53 Å2 / Biso mean: 21.2584 Å2 / Biso min: 3.67 Å2
Refinement stepCycle: final / Resolution: 1.98→60.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms30847 0 696 3560 35103
Biso mean--15.23 30.69 -
Num. residues----4039
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.98-20.29513870.2627000738777
2-2.030.28684030.24796876727977
2.03-2.050.29123460.24447001734776
2.05-2.080.27743730.24596817719076
2.08-2.10.2673710.23056978734977
2.1-2.130.27153650.23296921728677
2.13-2.160.26633680.2237018738677
2.16-2.20.26684180.21836894731278
2.2-2.230.25673820.20857071745378
2.23-2.270.23973820.20897167754979
2.27-2.310.2493470.20977195754279
2.31-2.350.24313940.20347380777481
2.35-2.390.24373950.19927500789583
2.39-2.440.24964050.19217670807585
2.44-2.490.24114070.1947935834287
2.49-2.550.20274390.19378130856990
2.55-2.620.23724410.19428268870992
2.62-2.690.23374300.19578592902294
2.69-2.770.22034610.19658801926297
2.77-2.860.24924860.19498920940698
2.86-2.960.22344900.18699004949499
2.96-3.080.22174980.181690549552100
3.08-3.220.20144830.177890489531100
3.22-3.390.21245160.175191109626100
3.39-3.60.20334590.162591079566100
3.6-3.880.17884410.15291369577100
3.88-4.270.18255020.144890969598100
4.27-4.880.17234930.145791239616100
4.88-6.150.20634240.16692229646100
6.15-60.530.1844700.1629209967999
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)
11.05-0.124-0.28510.32360.11880.41270.0022-0.0350.05390.0505-0.023-0.0364-0.04040.03230.01770.1525-0.0157-0.0230.07680.00080.103332.171567.581576.4082
21.68420.14331.07550.13190.36741.6602-0.0021-0.13260.04550.08710.00210.00910.0093-0.01390.01240.17260.00640.02360.1006-0.00030.142119.618480.609798.3502
30.5504-0.2094-0.20830.39920.07820.71960.04220.0999-0.0437-0.0504-0.0454-0.00510.0169-0.02080.00550.0924-0.0015-0.03720.09690.0030.123520.729354.323852.8105
41.35140.1150.34530.6132-0.21881.0297-0.02410.03050.3635-0.0386-0.0272-0.0262-0.3267-0.0195-0.01150.19270.0015-0.01010.09940.01570.169546.926375.153262.3583
51.1474-0.10960.33690.3264-0.13150.52010.0105-0.0212-0.06070.04390.00970.02980.04810.0011-0.01870.1409-0.012-0.00880.0946-0.00540.091346.401346.867484.8089
61.3243-0.3642-1.06580.21380.47051.36080.0131-0.18840.07780.06480.0196-0.0438-0.05850.1258-0.03470.1692-0.0087-0.05350.15650.02220.146256.415750.7394107.6602
71.2662-0.0276-0.3450.47050.11450.3461-0.00230.0382-0.1365-0.00750.00520.00780.09410.0047-0.01440.12-0.001-0.05030.0947-0.01150.116145.840342.985258.7633
80.89230.0572-0.42870.1314-0.12480.494-0.00960.04650.0604-0.0390.01070.0486-0.0061-0.037-0.00080.13720.0157-0.01330.0916-0.02550.119520.143795.295-8.9845
90.75260.28460.51150.62760.25610.9586-0.07870.1920.0347-0.1510.03990.0533-0.07590.07140.03010.22090.0038-0.01210.2145-0.00140.181737.8789100.2035-30.523
101.5704-0.1904-0.2452.12730.12752.0415-0.1134-0.02310.0817-0.0618-0.01240.0483-0.1917-0.02170.12230.1858-0.0362-0.02170.3381-0.03730.204217.606791.0454-33.1147
111.48280.39320.76750.41550.46390.79510.0159-0.0185-0.23010.00650.0172-0.01320.1904-0.0468-0.02990.21710.00120.02890.17770.00810.19428.716682.3489-34.5199
120.17430.04350.06960.2776-0.09030.77870.017-0.03570.02960.03-0.0028-0.0406-0.01390.1189-0.01610.0770.0088-0.00950.105-0.02840.131637.468594.485619.0538
131.38331.15590.65540.92790.5330.40740.0782-0.2431-0.16220.2925-0.0387-0.1580.08-0.0319-0.04830.16030.0078-0.00820.1893-0.02490.161623.769598.762237.6861
140.52030.417-0.270.78010.0830.2667-0.01620.03620.1369-0.10890.03050.0418-0.0807-0.11280.0020.09790.0284-0.00710.1338-0.00740.135218.3075101.846911.7444
151.09250.03120.55640.83430.34090.5432-0.0130.2010.2345-0.11960.0226-0.0062-0.23770.03570.00060.1502-0.00240.01180.11390.02310.18062.1225108.49360.7191
160.86340.23120.25920.42090.0910.34360.02010.0349-0.1267-0.0406-0.0024-0.04470.05030.0216-0.00930.11280.0190.0030.0774-0.02890.10412.606172.3624-0.2862
170.3330.00630.00450.54080.37230.5478-0.00810.1251-0.073-0.11920.00550.02150.0211-0.00860.00080.1540.0007-0.01790.1438-0.00110.1581-8.251668.801-11.0222
181.5206-0.2102-0.4330.1424-0.1040.6051-0.0485-0.1213-0.10850.06960.0324-0.00080.08330.0342-0.00120.0982-0.0155-0.02810.0812-0.00220.08686.38583.799723.7915
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 196 )A2 - 196
2X-RAY DIFFRACTION2chain 'A' and (resid 197 through 488 )A197 - 488
3X-RAY DIFFRACTION3chain 'A' and (resid 489 through 879 )A489 - 879
4X-RAY DIFFRACTION4chain 'A' and (resid 880 through 1017 )A880 - 1017
5X-RAY DIFFRACTION5chain 'B' and (resid 3 through 237 )B3 - 237
6X-RAY DIFFRACTION6chain 'B' and (resid 238 through 511 )B238 - 511
7X-RAY DIFFRACTION7chain 'B' and (resid 512 through 1018 )B512 - 1018
8X-RAY DIFFRACTION8chain 'C' and (resid 3 through 237 )C3 - 237
9X-RAY DIFFRACTION9chain 'C' and (resid 238 through 302 )C238 - 302
10X-RAY DIFFRACTION10chain 'C' and (resid 303 through 373 )C303 - 373
11X-RAY DIFFRACTION11chain 'C' and (resid 374 through 488 )C374 - 488
12X-RAY DIFFRACTION12chain 'C' and (resid 489 through 668 )C489 - 668
13X-RAY DIFFRACTION13chain 'C' and (resid 669 through 750 )C669 - 750
14X-RAY DIFFRACTION14chain 'C' and (resid 751 through 879 )C751 - 879
15X-RAY DIFFRACTION15chain 'C' and (resid 880 through 1017 )C880 - 1017
16X-RAY DIFFRACTION16chain 'D' and (resid 3 through 237 )D3 - 237
17X-RAY DIFFRACTION17chain 'D' and (resid 238 through 606 )D238 - 606
18X-RAY DIFFRACTION18chain 'D' and (resid 607 through 1019 )D607 - 1019

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