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- PDB-4oqv: High resolution crystal structure of human dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 4oqv
TitleHigh resolution crystal structure of human dihydroorotate dehydrogenase bound with DSM338 (N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Alpha/Beta Barrel / REDOX / DEHYDROGENASE / FMN / mitochondrial membrane / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase activity / dihydroorotase activity / Pyrimidine biosynthesis / UDP biosynthetic process / 'de novo' UMP biosynthetic process / 'de novo' pyrimidine nucleobase biosynthetic process / mitochondrial inner membrane ...pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase activity / dihydroorotase activity / Pyrimidine biosynthesis / UDP biosynthetic process / 'de novo' UMP biosynthetic process / 'de novo' pyrimidine nucleobase biosynthetic process / mitochondrial inner membrane / mitochondrion / nucleoplasm / cytosol
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-2V6 / ACETIC ACID / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.23 Å
AuthorsDeng, X. / Phillips, M.A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors.
Authors: Deng, X. / Kokkonda, S. / El Mazouni, F. / White, J. / Burrows, J.N. / Kaminsky, W. / Charman, S.A. / Matthews, D. / Rathod, P.K. / Phillips, M.A.
History
DepositionFeb 10, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 4, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,48810
Polymers41,1241
Non-polymers1,3649
Water6,449358
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.936, 90.936, 121.938
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Dihydroorotate dehydrogenase (quinone), mitochondrial / DHOdehase / Dihydroorotate oxidase


Mass: 41123.883 Da / Num. of mol.: 1 / Fragment: UNP residues 32-395
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH, Dihydroorotate Dehydrogenases / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): bl21
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 8 types, 367 molecules

#2: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#3: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#4: Chemical ChemComp-2V6 / N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine


Mass: 397.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H7F8N5
#5: Chemical ChemComp-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H4O2
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#8: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 358 / 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: 3.54 Å3/Da / Density % sol: 65.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.4
Details: 1.76 M Ammonium sulfate, 0.1 M Sodium Acetate, pH 5.4, 1.9 M NaCl, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 21, 2011
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.23→50 Å / Num. all: 168450 / Num. obs: 168235 / % possible obs: 99.8 % / Observed criterion σ(F): 2.7 / Observed criterion σ(I): 2.7 / Redundancy: 7.1 % / Biso Wilson estimate: 10.6 Å2 / Rsym value: 0.057 / Net I/σ(I): 29.6
Reflection shellResolution: 1.23→1.25 Å / Redundancy: 6 % / Mean I/σ(I) obs: 2.7 / Num. unique all: 8270 / Rsym value: 0.612 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASESphasing
REFMAC5.6.0117refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementResolution: 1.23→30 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.97 / SU B: 0.728 / SU ML: 0.015 / Cross valid method: THROUGHOUT / ESU R: 0.028 / ESU R Free: 0.028 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.15741 8445 5 %RANDOM
Rwork0.14137 ---
obs0.14217 159728 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.67 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å2-0.07 Å20 Å2
2---0.13 Å20 Å2
3---0.2 Å2
Refinement stepCycle: LAST / Resolution: 1.23→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2703 0 90 358 3151
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0290.0192932
X-RAY DIFFRACTIONr_bond_other_d0.0090.022040
X-RAY DIFFRACTIONr_angle_refined_deg2.4882.0153996
X-RAY DIFFRACTIONr_angle_other_deg1.30334959
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1545377
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.89922.992127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.05415502
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0761530
X-RAY DIFFRACTIONr_chiral_restr0.1560.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0210.0213263
X-RAY DIFFRACTIONr_gen_planes_other0.0150.02593
X-RAY DIFFRACTIONr_rigid_bond_restr9.04134971
X-RAY DIFFRACTIONr_sphericity_free82.092590
X-RAY DIFFRACTIONr_sphericity_bonded23.70955187
LS refinement shellResolution: 1.23→1.262 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.263 569 -
Rwork0.232 11058 -
obs--97.85 %
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)
11.34260.43633.04170.9422.583910.914-0.66860.1950.49010.45750.00870.00480.07530.20490.65990.78810.0052-0.17380.23940.10130.45054.7647-20.7214-7.6303
22.75011.04240.32874.03910.80924.2820.05840.340.3202-0.2319-0.023-0.2064-0.48410.2639-0.03540.0678-0.01620.03440.10980.02930.07859.3485-34.8062-4.2551
323.5306-9.6761-10.201114.90074.18024.82850.09420.63980.66960.3127-0.0742-0.6398-0.290.0268-0.020.3346-0.1515-0.09860.34730.0870.36878.318-18.68657.0839
410.6385.6397-7.283212.1224-4.19585.54690.1781-0.4220.23760.4315-0.2952-0.471-0.50890.43310.11710.2811-0.1047-0.18280.11270.01710.217-1.7492-18.360518.0817
50.9338-0.11390.37650.81220.05181.11440.01810.02090.0214-0.0023-0.0228-0.0746-0.00230.11970.00470.0204-0.00060.01070.05850.01280.04332.2568-39.90576.5774
61.5516-0.4421-0.13882.158-0.21411.8291-0.0311-0.0194-0.024-0.0076-0.0025-0.0020.0681-0.02120.03360.02160.0092-0.00580.06170.00970.00725.071-43.607219.5433
79.65170.81452.53551.1579-0.34412.19610.06150.0443-0.2555-0.06530.02380.13970.0667-0.1283-0.08540.04150.02060.00850.06530.01810.0476-6.6223-47.729728.2211
80.4086-0.17080.1920.2208-0.0340.26330.0037-0.0782-0.03810.0265-0.00320.02990.0201-0.0827-0.00050.02940.00160.00090.04590.00140.0385-13.6191-39.445110.7013
91.6888-0.57750.00712.18580.4371.6360.0242-0.00270.1983-0.04660.0035-0.0737-0.2461-0.0078-0.02770.0439-0.0005-0.0020.0212-0.00040.038-7.5377-24.53618.2874
1013.38720.5307-4.107712.3257-0.05821.6193-0.0756-1.24170.84241.34930.28940.1004-0.18590.1505-0.21380.28520.1882-0.02380.2805-0.09080.1066-21.0128-23.393116.8513
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A35 - 37
2X-RAY DIFFRACTION2A38 - 69
3X-RAY DIFFRACTION3A70 - 74
4X-RAY DIFFRACTION4A75 - 82
5X-RAY DIFFRACTION5A83 - 152
6X-RAY DIFFRACTION6A153 - 215
7X-RAY DIFFRACTION7A226 - 246
8X-RAY DIFFRACTION8A247 - 326
9X-RAY DIFFRACTION9A327 - 391
10X-RAY DIFFRACTION10A392 - 395

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