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- PDB-5k9c: Crystal structure of human dihydroorotate dehydrogenase with ML390 -

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Basic information

Entry
Database: PDB / ID: 5k9c
TitleCrystal structure of human dihydroorotate dehydrogenase with ML390
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Oxidoreductase / alpha/beta barrel / inhibitor / 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
ACETATE ION / Chem-FNR / Chem-MLJ / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.66 Å
AuthorsLewis, T.A. / Sykes, D.B. / Law, J.M. / Munoz, B. / Scadden, D.T. / Rustiguel, J.K. / Nonato, M.C. / Schreiber, S.L.
CitationJournal: ACS Med Chem Lett / Year: 2016
Title: Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.
Authors: Lewis, T.A. / Sykes, D.B. / Law, J.M. / Munoz, B. / Rustiguel, J.K. / Nonato, M.C. / Scadden, D.T. / Schreiber, S.L.
History
DepositionMay 31, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2017Group: Database references
Revision 1.2Sep 27, 2023Group: 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
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 (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,49712
Polymers39,9441
Non-polymers1,55311
Water6,125340
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.900, 89.900, 121.771
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-840-

HOH

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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: 39943.613 Da / Num. of mol.: 1 / Fragment: residues 29-395
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Plasmid: pET28a / Details (production host): pET28a modified vector / Production host: Escherichia coli (E. coli)
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 8 types, 351 molecules

#2: Chemical ChemComp-FNR / 1-DEOXY-1-(7,8-DIMETHYL-2,4-DIOXO-3,4-DIHYDRO-2H-BENZO[G]PTERIDIN-1-ID-10(5H)-YL)-5-O-PHOSPHONATO-D-RIBITOL / TWO ELECTRON REDUCED FLAVIN MONONUCLEOTIDE


Mass: 458.360 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H23N4O9P
#3: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#4: Chemical ChemComp-MLJ / ~{N}-[3-oxidanylidene-3-[[(1~{R})-1,2,3,4-tetrahydronaphthalen-1-yl]amino]propyl]-4-(trifluoromethyloxy)benzamide


Mass: 406.398 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21F3N2O3
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 340 / 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: 3.43 Å3/Da / Density % sol: 64.2 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 4.8
Details: 0.1 M sodium acetate trihydrate pH 4.8 1.9 M ammonium sulfate 30% (v/v) glycerol
PH range: 4.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: LNLS / Beamline: W01B-MX2 / Wavelength: 1.4586 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Mar 10, 2015
RadiationMonochromator: Si(111) double-crystal monochromator and toroidal bendable mirror
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.4586 Å / Relative weight: 1
ReflectionResolution: 1.66→25.952 Å / Num. obs: 67579 / % possible obs: 99.8 % / Redundancy: 15.1 % / Biso Wilson estimate: 14.33 Å2 / CC1/2: 0.998 / Rsym value: 0.097 / Net I/σ(I): 18.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.66-1.757.30.4071.4198.5
1.75-1.8611.30.3121.81100
1.86-1.9812.90.2282.31100
1.98-2.1415.80.1494.21100
2.14-2.3519.10.12351100
2.35-2.6218.60.1145.11100
2.62-3.0318.70.0985.61100
3.03-3.7119.70.0836.61100
3.71-5.2519.10.0688.21100
5.25-25.95218.60.0619.4199.2

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation7.27 Å25.95 Å
Translation7.27 Å25.95 Å

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Processing

Software
NameVersionClassification
iMOSFLM7.2.1data reduction
SCALA3.3.22data scaling
PHASER2.6.0phasing
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1D3G

1d3g


Resolution: 1.66→25.952 Å / SU ML: 0.1 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 12.65
Details: THE AUTHORS STATE THAT ELECTRON DENSITY ANALYSIS REVEALED THAT THE MAIN CHAIN HAD A DOUBLE CONFORMATION ( FROM RESIDUE 211 TO 226), DUE TO ITS EXPECTED FLEXIBILITY (AS A CATALYTIC LOOP). ...Details: THE AUTHORS STATE THAT ELECTRON DENSITY ANALYSIS REVEALED THAT THE MAIN CHAIN HAD A DOUBLE CONFORMATION ( FROM RESIDUE 211 TO 226), DUE TO ITS EXPECTED FLEXIBILITY (AS A CATALYTIC LOOP). VAL213 SHOWED A VERY CLEAR ELECTRON DENSITY IN CONFORMATION B, BUT IN CONTRAST, CONFORMATION A WAS DOMINANT FOR RESIDUES FROM 214 TO 218. THE VAL213 CONFORMER AND THE SER214 A CONFORMER WERE CONFLICTING AS A CONSEQUENCE OF THE DIFFERENT LOOP ARRANGEMENTS (OPEN AND CLOSED CONFORMATIONS). TAKING ALL THESE INTO ACCOUNT, THE AUTHORS STATE THAT THE VAL213 DOUBLE CONFORMATION IS THE SOLUTION THAT BETTER FITS THE DATASET AND THEREFORE, VAL213 (B CONFORMER) AND SER214 (A CONFORMER) ARE NOT LINKED.
RfactorNum. reflection% reflectionSelection details
Rfree0.1496 3227 4.78 %random selection
Rwork0.131 ---
obs0.1319 67468 99.66 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 136.79 Å2 / Biso mean: 23.5645 Å2 / Biso min: 5.99 Å2
Refinement stepCycle: final / Resolution: 1.66→25.952 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2665 0 227 345 3237
Biso mean--23.06 36.16 -
Num. residues----355
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012986
X-RAY DIFFRACTIONf_angle_d1.0984074
X-RAY DIFFRACTIONf_chiral_restr0.074454
X-RAY DIFFRACTIONf_plane_restr0.008533
X-RAY DIFFRACTIONf_dihedral_angle_d14.3571118
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 23

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.66-1.68480.21451040.17512636274095
1.6848-1.71110.16591040.16062766287098
1.7111-1.73920.15071620.14742744290699
1.7392-1.76920.181450.136227462891100
1.7692-1.80130.15171160.138628202936100
1.8013-1.8360.1571430.136227302873100
1.836-1.87340.1491430.135828032946100
1.8734-1.91420.14281500.133227382888100
1.9142-1.95870.14791570.125127612918100
1.9587-2.00760.14051290.116527782907100
2.0076-2.06190.12521230.117128232946100
2.0619-2.12260.12261570.114727522909100
2.1226-2.1910.12981520.109128192971100
2.191-2.26930.1211190.109427692888100
2.2693-2.36010.13671470.113628202967100
2.3601-2.46740.12881390.118127802919100
2.4674-2.59740.15251580.119228012959100
2.5974-2.760.15071120.125128242936100
2.76-2.97280.1341730.122427922965100
2.9728-3.27140.13511560.125628122968100
3.2714-3.74360.15381310.127128592990100
3.7436-4.71190.14941440.132628973041100
4.7119-25.95510.20521630.182129713134100
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)
10.1769-0.0891-0.08620.0450.03780.40490.06290.2829-0.3095-0.0157-0.07750.09870.2651-0.2775-0.0180.194-0.0108-0.03130.3141-0.04370.241136.2632-46.5998119.8611
20.10410.01740.0940.0137-0.00120.1114-0.0931-0.0859-0.13790.1365-0.00440.10670.0832-0.0081-0.02220.15650.00910.0590.13370.03660.143946.1814-54.0039140.3249
30.7218-0.2126-0.43080.37890.21350.76640.0089-0.08030.00420.0058-0.0060.03010.01230.016-00.04820.00680.00220.09350.00270.070549.6612-39.965134.0486
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 35 through 76 )A35 - 76
2X-RAY DIFFRACTION2chain 'A' and (resid 77 through 94 )A77 - 94
3X-RAY DIFFRACTION3chain 'A' and (resid 95 through 396 )A95 - 396

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