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- PDB-6i4b: Plasmodium falciparum dihydroorotate dehydrogenase (DHODH) co-cry... -

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Basic information

Entry
Database: PDB / ID: 6i4b
TitlePlasmodium falciparum dihydroorotate dehydrogenase (DHODH) co-crystallized with 3-Hydroxy-1-methyl-5-((3-(trifluoromethyl)phenoxy)methyl)-1H-pyrazole-4-carboxylic acid
ComponentsDihydroorotate dehydrogenase
KeywordsOXIDOREDUCTASE / dhodh / plasmodium falciparum dhodh
Function / homology
Function and homology information


Pyrimidine biosynthesis / pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase activity / 'de novo' UMP biosynthetic process / 'de novo' pyrimidine nucleobase biosynthetic process / mitochondrial inner membrane / nucleotide binding / plasma membrane
Similarity search - Function
Dihydroorotate dehydrogenase, class 2 / Dihydroorotate dehydrogenase signature 1. / Dihydroorotate dehydrogenase signature 2. / Dihydroorotate dehydrogenase, conserved site / : / Dihydroorotate dehydrogenase domain / Dihydroorotate dehydrogenase / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel ...Dihydroorotate dehydrogenase, class 2 / Dihydroorotate dehydrogenase signature 1. / Dihydroorotate dehydrogenase signature 2. / Dihydroorotate dehydrogenase, conserved site / : / Dihydroorotate dehydrogenase domain / Dihydroorotate dehydrogenase / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-E2N / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.98 Å
AuthorsGoyal, P. / Sainas, S. / Pippione, A.C. / Boschi, D. / Al-Kadaraghi, S.
CitationJournal: Eur J Med Chem / Year: 2018
Title: Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies.
Authors: Pippione, A.C. / Sainas, S. / Goyal, P. / Fritzson, I. / Cassiano, G.C. / Giraudo, A. / Giorgis, M. / Tavella, T.A. / Bagnati, R. / Rolando, B. / Caing-Carlsson, R. / Costa, F.T.M. / ...Authors: Pippione, A.C. / Sainas, S. / Goyal, P. / Fritzson, I. / Cassiano, G.C. / Giraudo, A. / Giorgis, M. / Tavella, T.A. / Bagnati, R. / Rolando, B. / Caing-Carlsson, R. / Costa, F.T.M. / Andrade, C.H. / Al-Karadaghi, S. / Boschi, D. / Friemann, R. / Lolli, M.L.
History
DepositionNov 9, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 19, 2018Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Dihydroorotate dehydrogenase
B: Dihydroorotate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,5628
Polymers91,7052
Non-polymers1,8576
Water5,260292
1
A: Dihydroorotate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7814
Polymers45,8521
Non-polymers9293
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dihydroorotate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7814
Polymers45,8521
Non-polymers9293
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.607, 158.121, 61.753
Angle α, β, γ (deg.)90.000, 105.670, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Dihydroorotate dehydrogenase


Mass: 45852.461 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: dhod / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q54A96, UniProt: Q08210*PLUS
#2: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21N4O9P
#3: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H4N2O4
#4: Chemical ChemComp-E2N / 1-methyl-3-oxidanyl-5-[[3-(trifluoromethyl)phenoxy]methyl]pyrazole-4-carboxylic acid


Mass: 316.233 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H11F3N2O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 292 / 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: 2.76 Å3/Da / Density % sol: 55.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Tris-HCl (pH 7.5-9.5), 35 % (w/v) PEG 4000 and 50 mM sodium formate
PH range: 7.5-9.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-2 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.98→79.061 Å / Num. obs: 64341 / % possible obs: 99.2 % / Redundancy: 7.2 % / Biso Wilson estimate: 32.38 Å2 / Rpim(I) all: 0.044 / Rrim(I) all: 0.119 / Rsym value: 0.11 / Net I/av σ(I): 5.3 / Net I/σ(I): 10.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.98-2.097.41.1340.794550.4451.2191.13499.9
2.09-2.217.40.8210.989550.3240.8830.82199.9
2.21-2.377.40.4981.683830.1960.5360.49899.9
2.37-2.567.30.3342.377790.1320.3590.33499.8
2.56-2.87.20.2153.671690.0860.2320.21599.3
2.8-3.1370.1345.563760.0540.1450.13497.9
3.13-3.616.30.0778.655100.0330.0840.07795.8
3.61-4.437.50.05810.748500.0230.0630.058100
4.43-6.267.40.05111.737810.020.0550.05199.9
6.26-48.7257.10.04310.820830.0180.0470.04399.6

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Processing

Software
NameVersionClassification
XDSdata reduction
SCALA3.3.21data scaling
PHENIX1.13_2998refinement
PDB_EXTRACT3.24data extraction
PHASERphasing
RefinementResolution: 1.98→48.725 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.12
RfactorNum. reflection% reflection
Rfree0.2262 3260 5.07 %
Rwork0.1921 --
obs0.1939 64264 99.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 129.79 Å2 / Biso mean: 48.5579 Å2 / Biso min: 22.44 Å2
Refinement stepCycle: final / Resolution: 1.98→48.725 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5988 0 128 292 6408
Biso mean--47.47 44.82 -
Num. residues----755
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 23

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.98-2.00960.37211460.335926852831100
2.0096-2.0410.29791480.32226672815100
2.041-2.07440.32561350.298826742809100
2.0744-2.11020.31791400.284126862826100
2.1102-2.14860.31311410.267726332774100
2.1486-2.18990.39071510.313126622813100
2.1899-2.23460.26161500.228526402790100
2.2346-2.28320.26851460.22612666281299
2.2832-2.33630.27131350.210326252760100
2.3363-2.39470.25151290.216427032832100
2.3947-2.45950.25241440.197926632807100
2.4595-2.53190.2781440.19592659280399
2.5319-2.61360.26661270.197326512778100
2.6136-2.7070.23491410.18922655279699
2.707-2.81530.22831540.18252667282199
2.8153-2.94350.21091390.18082614275398
2.9435-3.09860.24351230.17992611273497
3.0986-3.29270.20571440.18232574271897
3.2927-3.54690.19331230.18292534265794
3.5469-3.90370.22851580.174726662824100
3.9037-4.46820.19551410.163126872828100
4.4682-5.62820.18371550.159326862841100
5.6282-48.73960.17921460.170526962842100
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)
13.07550.1139-2.64682.68140.41413.74970.1286-0.5521-0.98770.1299-0.118-0.10390.66910.57290.15911.09120.0549-0.40230.45050.08080.780619.0547-43.804632.4155
24.5443-0.59552.56263.3332-2.5173.23270.40890.0843-0.45590.0254-0.034-0.55210.0670.7702-0.13140.73560.027-0.26510.32880.01520.576622.7762-32.805229.5938
31.72110.13140.81821.9127-0.05812.43110.1285-0.0858-0.18210.10380.0180.01750.1669-0.074-0.1210.43560.0208-0.11230.25550.01170.250510.8623-18.997222.9167
41.86460.6890.64462.630.75272.7759-0.144-0.27120.32380.3279-0.01590.0585-0.87540.10320.18210.9915-0.0953-0.32710.41390.01290.534733.075224.371763.4456
50.38550.5119-0.21761.51870.04570.343-0.32780.05730.26650.2493-0.0207-0.1473-0.61140.35010.19350.463-0.1125-0.17160.33850.07250.344333.03339.879956.6121
62.3054-0.380.26082.32060.41684.59030.05930.0589-0.1353-0.01850.00090.05770.23420.1465-0.02170.2706-0.0303-0.09390.20220.03030.229828.4465-3.28553.6702
71.0063-0.21910.14772.72630.14921.1414-0.21810.34190.3742-0.272-0.1632-0.1561-0.71350.58250.28920.5758-0.1629-0.14420.46220.12050.375934.737813.570142.5495
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 157 through 178 )A157 - 178
2X-RAY DIFFRACTION2chain 'A' and (resid 179 through 205 )A179 - 205
3X-RAY DIFFRACTION3chain 'A' and (resid 206 through 567 )A206 - 567
4X-RAY DIFFRACTION4chain 'B' and (resid 158 through 205 )B158 - 205
5X-RAY DIFFRACTION5chain 'B' and (resid 206 through 282 )B206 - 282
6X-RAY DIFFRACTION6chain 'B' and (resid 283 through 449 )B283 - 449
7X-RAY DIFFRACTION7chain 'B' and (resid 450 through 567 )B450 - 567

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