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- PDB-6vnd: Quaternary Complex of human dihydroorotate dehydrogenase (DHODH) ... -

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Basic information

Entry
Database: PDB / ID: 6vnd
TitleQuaternary Complex of human dihydroorotate dehydrogenase (DHODH) with flavin mononucleotide (FMN), orotic acid and AG-636
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrialDihydroorotate dehydrogenase (quinone)
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / DHODH / OXIDOREDUCTASE / FMN binding / Inhibitor / Mitochondria inner membrane / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase (quinone) / 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) activity / dihydroorotate dehydrogenase (quinone) / 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-type TIM barrel
Similarity search - Domain/homology
ACETATE ION / DECYLAMINE-N,N-DIMETHYL-N-OXIDE / UNDECYLAMINE-N,N-DIMETHYL-N-OXIDE / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Chem-R4P / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsPadyana, A. / Jin, L.
CitationJournal: Mol.Cancer Ther. / Year: 2020
Title: Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase.
Authors: McDonald, G. / Chubukov, V. / Coco, J. / Truskowski, K. / Narayanaswamy, R. / Choe, S. / Steadman, M. / Artin, E. / Padyana, A.K. / Jin, L. / Ronseaux, S. / Locuson, C. / Fan, Z.P. / ...Authors: McDonald, G. / Chubukov, V. / Coco, J. / Truskowski, K. / Narayanaswamy, R. / Choe, S. / Steadman, M. / Artin, E. / Padyana, A.K. / Jin, L. / Ronseaux, S. / Locuson, C. / Fan, Z.P. / Erdmann, T. / Mann, A. / Hayes, S. / Fletcher, M. / Nellore, K. / Rao, S.S. / Subramanya, H. / Reddy, K.S. / Panigrahi, S.K. / Antony, T. / Gopinath, S. / Sui, Z. / Nagaraja, N. / Dang, L. / Lenz, G. / Hurov, J. / Biller, S.A. / Murtie, J. / Marks, K.M. / Ulanet, D.B.
History
DepositionJan 29, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 4, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 16, 2020Group: 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 / _citation_author.name
Revision 1.2Oct 11, 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_atoms
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)42,53721
Polymers39,9141
Non-polymers2,62320
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.526, 90.526, 123.761
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 39913.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Production host: Escherichia coli (E. coli)
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 10 types, 248 molecules

#2: Chemical ChemComp-R4P / 1-methyl-5-(2'-methyl[1,1'-biphenyl]-4-yl)-1H-benzotriazole-7-carboxylic acid


Mass: 343.379 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DET / UNDECYLAMINE-N,N-DIMETHYL-N-OXIDE


Mass: 215.375 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H29NO
#4: Chemical ChemComp-DDQ / DECYLAMINE-N,N-DIMETHYL-N-OXIDE


Mass: 201.349 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H27NO
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#7: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


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


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#9: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#10: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#11: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 228 / 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: 3.51 Å3/Da / Density % sol: 64.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.8
Details: 2.5 M ammonium sulfate, 30% glycerol, 0.1 M sodium acetate, pH 4.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.97→50 Å / Num. obs: 38783 / % possible obs: 92.7 % / Redundancy: 3.4 % / Biso Wilson estimate: 28.78 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 13.4
Reflection shellResolution: 1.97→2 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.52 / Num. unique obs: 1953 / % possible all: 93.9

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZWS

3zws


Resolution: 1.97→28.78 Å / SU ML: 0.1744 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 17.1363
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1901 1885 4.86 %
Rwork0.1554 36886 -
obs0.1571 38771 92.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.39 Å2
Refinement stepCycle: LAST / Resolution: 1.97→28.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2785 0 178 228 3191
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01933071
X-RAY DIFFRACTIONf_angle_d1.38114146
X-RAY DIFFRACTIONf_chiral_restr0.0986445
X-RAY DIFFRACTIONf_plane_restr0.0098562
X-RAY DIFFRACTIONf_dihedral_angle_d18.533508
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.97-2.030.22131570.20872848X-RAY DIFFRACTION94.47
2.03-2.090.24311440.19712930X-RAY DIFFRACTION97
2.09-2.150.20941820.1832918X-RAY DIFFRACTION97.3
2.15-2.230.22751580.16672889X-RAY DIFFRACTION97.1
2.23-2.320.19131270.162987X-RAY DIFFRACTION96.74
2.32-2.430.20441570.15072866X-RAY DIFFRACTION95.51
2.43-2.550.17371580.13952856X-RAY DIFFRACTION94.13
2.55-2.710.19421230.14392899X-RAY DIFFRACTION94.59
2.71-2.920.19521390.13342866X-RAY DIFFRACTION93.5
2.92-3.220.15831160.13052823X-RAY DIFFRACTION91.64
3.22-3.680.15881290.13362665X-RAY DIFFRACTION86.26
3.68-4.630.161540.14172713X-RAY DIFFRACTION87.3
4.64-28.780.22941410.19542626X-RAY DIFFRACTION81.22
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)
10.147339490392-0.153649819783-0.04873696666130.3658545260.0850803533820.3089197012980.305444978139-0.0108558858462-0.1289313807420.5771844747760.03620482863630.409329383410.444970206743-0.433112707453-0.002008354306510.5376655084010.02702773774830.06631186687340.531237908120.1785263849970.43271562822726.67238590638.905762349898.60996252451
20.368585326284-0.503026411016-0.3777351739540.8739083193770.165479845121.02438096991-0.1357701557-0.314093701148-0.549717600464-0.2370648713810.166013850750.4510416741870.458808450371-0.3538651006360.004447136437940.463430131450.0260393080591-0.01551257932480.3567099620270.09103522512050.48223012389131.60489379086.36434314314-2.85250893122
30.460301166278-0.0159888321711-0.107662975291.14852839822-0.2829809651910.489458608817-0.1258195659680.503293578461-0.60195427006-0.667547854484-0.01955187837520.3106842285950.35801328197-0.116655444769-0.009310639892690.343371039676-0.0004981551184790.0109495357520.34697967207-0.1014410541440.34029774424520.429647920713.420759408-19.0818638928
40.777830295918-0.3962447806070.07354307214180.8244311623620.3814662140851.290236598020.0177001909784-0.09705436809980.002975984965840.01418282686240.0401170151931-0.125763099180.187251414620.2029343474620.0001124830123590.2111906693540.02884559042140.0018745950760.199603140666-0.009960149587660.21943121467538.15036752618.4598969612-5.09188622007
52.94054905071-0.81404078744-0.2732628949691.24721128426-1.324448404752.834107820770.09739302279980.07656950602250.3074606063690.0202209184439-0.171282514498-0.237780501883-0.3070489922430.2203363125230.0007183649521650.243749166030.03644544734230.0500597954850.220243779885-0.003827162702530.19866591699539.656298984322.6126962358-20.12742289
61.32664682426-0.341215745527-0.3930431120740.3435953626440.0004266853961661.222996867620.03235959334030.08052018844120.0865583560271-0.11684623692-0.0840774997805-0.0025908063346-0.198694061554-0.143049880279-0.0002479529673930.2093446892650.024527527315-0.003922659080750.151266027053-0.006068396145640.1931622059628.574852609831.0032252931-11.9118129879
72.261899314140.0164242757984-0.4796012267582.281731003930.462098922161.24118313080.02203188434670.0251000804437-0.132156060943-0.0242852096218-0.06164123872270.3145630628740.119029119127-0.377218574763-0.0003829316887710.173879391490.003441361232670.006149087237140.21956257853-0.03751927822540.19116032892617.022376727620.2569593566-9.64913089695
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 30 through 50 )
2X-RAY DIFFRACTION2chain 'A' and (resid 51 through 75 )
3X-RAY DIFFRACTION3chain 'A' and (resid 76 through 93 )
4X-RAY DIFFRACTION4chain 'A' and (resid 94 through 152 )
5X-RAY DIFFRACTION5chain 'A' and (resid 153 through 241 )
6X-RAY DIFFRACTION6chain 'A' and (resid 242 through 322 )
7X-RAY DIFFRACTION7chain 'A' and (resid 323 through 394 )

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