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- PDB-8pbn: Mutant R1789Q of the dihydroorotase domain of human CAD protein b... -

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Basic information

Entry
Database: PDB / ID: 8pbn
TitleMutant R1789Q of the dihydroorotase domain of human CAD protein bound to the inhibitor fluoorotate
ComponentsCAD protein
KeywordsHYDROLASE / Nucleotide metabolism / de novo pyrimidine synthesis / CAD disease / multienzymatic protein / zinc / carboxylated lysine / BIOSYNTHETIC PROTEIN
Function / homology
Function and homology information


aspartate binding / carbamoyl-phosphate synthase (glutamine-hydrolysing) / carbamoyl-phosphate synthase (ammonia) / carbamoyl-phosphate synthase (ammonia) activity / carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity / dihydroorotase / response to cortisol / citrulline biosynthetic process / aspartate carbamoyltransferase / glutaminase ...aspartate binding / carbamoyl-phosphate synthase (glutamine-hydrolysing) / carbamoyl-phosphate synthase (ammonia) / carbamoyl-phosphate synthase (ammonia) activity / carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity / dihydroorotase / response to cortisol / citrulline biosynthetic process / aspartate carbamoyltransferase / glutaminase / aspartate carbamoyltransferase activity / dihydroorotase activity / Pyrimidine biosynthesis / UDP biosynthetic process / glutaminase activity / glutamine metabolic process / UTP biosynthetic process / response to caffeine / response to starvation / response to amine / response to testosterone / 'de novo' UMP biosynthetic process / animal organ regeneration / 'de novo' pyrimidine nucleobase biosynthetic process / lactation / peptidyl-threonine phosphorylation / xenobiotic metabolic process / cellular response to epidermal growth factor stimulus / liver development / cell projection / female pregnancy / response to insulin / terminal bouton / nuclear matrix / heart development / protein autophosphorylation / protein kinase activity / neuronal cell body / enzyme binding / protein-containing complex / extracellular exosome / zinc ion binding / ATP binding / identical protein binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Carbamoyl-phosphate synthase small subunit, N-terminal domain / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain / Carbamoyl-phosphate synthase large subunit, CPSase domain / Carbamoyl-phosphate synthase, small subunit / Carbamoyl-phosphate synthase, large subunit / Carbamoyl-phosphate synthase small subunit, GATase1 domain / Carbamoyl-phosphate synthase small subunit, N-terminal domain superfamily / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain superfamily / Carbamoyl-phosphate synthase small chain, CPSase domain / Carbamoyl-phosphate synthetase large chain, oligomerisation domain ...Carbamoyl-phosphate synthase small subunit, N-terminal domain / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain / Carbamoyl-phosphate synthase large subunit, CPSase domain / Carbamoyl-phosphate synthase, small subunit / Carbamoyl-phosphate synthase, large subunit / Carbamoyl-phosphate synthase small subunit, GATase1 domain / Carbamoyl-phosphate synthase small subunit, N-terminal domain superfamily / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain superfamily / Carbamoyl-phosphate synthase small chain, CPSase domain / Carbamoyl-phosphate synthetase large chain, oligomerisation domain / Carbamoyl-phosphate synthetase large chain, oligomerisation domain / Carbamoyl-phosphate synthase small chain, CPSase domain / Dihydroorotase signature 1. / Dihydroorotase signature 2. / Dihydroorotase, conserved site / Methylglyoxal synthase-like domain / Methylglyoxal synthase-like domain superfamily / MGS-like domain / MGS-like domain profile. / MGS-like domain / Aspartate carbamoyltransferase / Aspartate and ornithine carbamoyltransferases signature. / Aspartate/ornithine carbamoyltransferase / Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain / Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding / Aspartate/ornithine carbamoyltransferase superfamily / Aspartate/ornithine carbamoyltransferase, Asp/Orn binding domain / Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain / Glutamine amidotransferase / Glutamine amidotransferase class-I / Glutamine amidotransferase type 1 domain profile. / Carbamoyl-phosphate synthase subdomain signature 1. / Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain / Carbamoyl-phosphate synthase L chain, ATP binding domain / Amidohydrolase family / Metal-dependent hydrolase, composite domain superfamily / Amidohydrolase-related / ATP-grasp fold, subdomain 1 / Pre-ATP-grasp domain superfamily / ATP-grasp fold / ATP-grasp fold profile. / Class I glutamine amidotransferase-like / Metal-dependent hydrolase / Carbamoyl-phosphate synthase subdomain signature 2.
Similarity search - Domain/homology
FORMIC ACID / Chem-FOT / Multifunctional protein CAD
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 Å
Authorsdel Cano-Ochoa, F. / Ramon-Maiques, S.
Funding support Spain, 3items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)PID2021-128468NB-I00 Spain
Other privateFundacion Ramon Areces, XX National Call Spain
Other governmentPostdoctoral fellow of the Generalitat Valenciana (APOSTD 2021) Spain
CitationJournal: J Inherit Metab Dis / Year: 2023
Title: Beyond genetics: Deciphering the impact of missense variants in CAD deficiency.
Authors: Del Cano-Ochoa, F. / Ng, B.G. / Rubio-Del-Campo, A. / Mahajan, S. / Wilson, M.P. / Vilar, M. / Rymen, D. / Sanchez-Pintos, P. / Kenny, J. / Ley Martos, M. / Campos, T. / Wortmann, S.B. / ...Authors: Del Cano-Ochoa, F. / Ng, B.G. / Rubio-Del-Campo, A. / Mahajan, S. / Wilson, M.P. / Vilar, M. / Rymen, D. / Sanchez-Pintos, P. / Kenny, J. / Ley Martos, M. / Campos, T. / Wortmann, S.B. / Freeze, H.H. / Ramon-Maiques, S.
History
DepositionJun 9, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 1, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.2Nov 22, 2023Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CAD protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,29210
Polymers39,6651
Non-polymers6279
Water5,332296
1
A: CAD protein
hetero molecules

A: CAD protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,58520
Polymers79,3312
Non-polymers1,25418
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_554-x,y,-z-1/21
Buried area6050 Å2
ΔGint-175 kcal/mol
Surface area24550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.933, 158.236, 61.673
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-1904-

FMT

21A-1904-

FMT

31A-2250-

HOH

41A-2291-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein CAD protein


Mass: 39665.363 Da / Num. of mol.: 1 / Mutation: R1789Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CAD / Plasmid: pOPIN-M-huDHO-R1789Q / Cell (production host): epithelial-like / Cell line (production host): HEK293 GnTI- / Organ (production host): Embryo / Production host: Homo sapiens (human) / Tissue (production host): Kidney
References: UniProt: P27708, carbamoyl-phosphate synthase (glutamine-hydrolysing), aspartate carbamoyltransferase, dihydroorotase

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Non-polymers , 5 types, 305 molecules

#2: Chemical ChemComp-FOT / 5-FLUORO-2,6-DIOXO-1,2,3,6-TETRAHYDROPYRIMIDINE-4-CARBOXYLIC ACID / 5-FLUOROOROTIC ACID


Mass: 174.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H3FN2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: CH2O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 296 / 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: 2.52 Å3/Da / Density % sol: 51.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100mM Tris-HCl pH7, 2.7 M sodium formate, 2 mM fluoroorotate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 29, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.71→47.05 Å / Num. obs: 288962 / % possible obs: 99.92 % / Redundancy: 6.7 % / Biso Wilson estimate: 22.78 Å2 / CC1/2: 0.999 / Net I/σ(I): 16.94
Reflection shellResolution: 1.714→1.775 Å / Mean I/σ(I) obs: 2.29 / Num. unique obs: 28941 / CC1/2: 0.849

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Processing

Software
NameVersionClassification
EDNAdata collection
autoPROCdata processing
PHASERv8.0phasing
REFMACv8.0refinement
PHENIX1.20.1_4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.71→47.05 Å / SU ML: 0.1889 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.6254
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1869 2223 5.12 %
Rwork0.1454 41191 -
obs0.1475 43414 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.27 Å2
Refinement stepCycle: LAST / Resolution: 1.71→47.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2741 0 35 296 3072
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00442988
X-RAY DIFFRACTIONf_angle_d0.89254107
X-RAY DIFFRACTIONf_chiral_restr0.0488467
X-RAY DIFFRACTIONf_plane_restr0.0089544
X-RAY DIFFRACTIONf_dihedral_angle_d7.4047431
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.71-1.750.28131330.22682519X-RAY DIFFRACTION99.92
1.75-1.790.24211330.20632524X-RAY DIFFRACTION99.96
1.79-1.840.28161280.19252575X-RAY DIFFRACTION100
1.84-1.890.30541510.19372538X-RAY DIFFRACTION100
1.89-1.940.20391130.17572555X-RAY DIFFRACTION99.89
1.94-20.25671490.14632552X-RAY DIFFRACTION99.93
2-2.080.20231310.13132552X-RAY DIFFRACTION99.96
2.08-2.160.15581410.12472546X-RAY DIFFRACTION99.93
2.16-2.260.20631330.12812570X-RAY DIFFRACTION99.96
2.26-2.380.17071260.13612581X-RAY DIFFRACTION99.89
2.38-2.520.16581580.13192547X-RAY DIFFRACTION100
2.53-2.720.1961430.13862578X-RAY DIFFRACTION100
2.72-2.990.20941320.15282608X-RAY DIFFRACTION100
2.99-3.430.19081390.14562618X-RAY DIFFRACTION99.96
3.43-4.320.1381470.12142609X-RAY DIFFRACTION99.96
4.32-100.17891660.15442719X-RAY DIFFRACTION99.59

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