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- PDB-5fi8: Crystal structure of plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 5fi8
TitleCrystal structure of plasmodium falciparum dihydroorotate dehydrogenase bounded with DSM422 (Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidine)
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrialDihydroorotate dehydrogenase (quinone)
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / FMN / alpha/beta barrel / inhibitor / OXIDOREDUCTASE / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
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
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 / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-5Y5 / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.32 Å
AuthorsDeng, X. / Kokkonda, S. / Tomchick, D. / Phillips, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U01AI075594 United States
CitationJournal: J.Med.Chem. / Year: 2016
Title: Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.
Authors: Kokkonda, S. / Deng, X. / White, K.L. / Coteron, J.M. / Marco, M. / de Las Heras, L. / White, J. / El Mazouni, F. / Tomchick, D.R. / Manjalanagara, K. / Rudra, K.R. / Chen, G. / Morizzi, J. ...Authors: Kokkonda, S. / Deng, X. / White, K.L. / Coteron, J.M. / Marco, M. / de Las Heras, L. / White, J. / El Mazouni, F. / Tomchick, D.R. / Manjalanagara, K. / Rudra, K.R. / Chen, G. / Morizzi, J. / Ryan, E. / Kaminsky, W. / Leroy, D. / Martinez-Martinez, M.S. / Jimenez-Diaz, M.B. / Bazaga, S.F. / Angulo-Barturen, I. / Waterson, D. / Burrows, J.N. / Matthews, D. / Charman, S.A. / Phillips, M.A. / Rathod, P.K.
History
DepositionDec 22, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 22, 2016Group: Database references
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 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)46,6505
Polymers45,3861
Non-polymers1,2644
Water1,17165
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.147, 86.147, 139.053
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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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: 45385.914 Da / Num. of mol.: 1 / Fragment: UNP residues 158-569
Source method: isolated from a genetically manipulated source
Details: Deletion of loop (384-413)
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7 / Gene: PFF0160c / Plasmid: pET28b / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 5 types, 69 molecules

#2: Chemical ChemComp-5Y5 / 2-[1,1-bis(fluoranyl)ethyl]-~{N}-[(2~{S})-7-bromanyl-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine


Mass: 422.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18BrF2N5
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


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


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#5: Chemical ChemComp-LDA / LAURYL DIMETHYLAMINE-N-OXIDE / Lauryldimethylamine oxide


Mass: 229.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H31NO / Comment: LDAO, detergent*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 3.28 Å3/Da / Density % sol: 66.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.2
Details: 0.16 M Ammonium sulfate, 0.1 M NaAcetate, pH 4.2, 9.5% PEG4000 (w/v), 24% Glycerol (v/v), and 10 mM DTT

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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: Apr 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.32→31.5 Å / Num. obs: 25308 / % possible obs: 99.5 % / Observed criterion σ(I): 1 / Redundancy: 12.5 % / Rsym value: 0.048 / Net I/σ(I): 43.4
Reflection shellResolution: 2.32→2.36 Å / Redundancy: 10.9 % / Mean I/σ(I) obs: 1 / % possible all: 0.88

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3I65

3i65


Resolution: 2.32→31.5 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2217 1085 5.09 %
Rwork0.1798 --
obs0.182 21296 84.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.32→31.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2882 0 84 65 3031
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043016
X-RAY DIFFRACTIONf_angle_d0.854064
X-RAY DIFFRACTIONf_dihedral_angle_d13.1941131
X-RAY DIFFRACTIONf_chiral_restr0.031450
X-RAY DIFFRACTIONf_plane_restr0.002508
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3219-2.42760.4307560.2384965X-RAY DIFFRACTION32
2.4276-2.55550.2856830.22781560X-RAY DIFFRACTION52
2.5555-2.71550.3051370.2432804X-RAY DIFFRACTION93
2.7155-2.9250.27451580.2232986X-RAY DIFFRACTION100
2.925-3.21910.2391510.20882986X-RAY DIFFRACTION100
3.2191-3.68430.20931780.18412973X-RAY DIFFRACTION100
3.6843-4.63950.19121680.14542998X-RAY DIFFRACTION100
4.6395-31.55560.17921540.14622939X-RAY DIFFRACTION97
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)
10.0130.0050.01480.01960.00970.01740.06090.080.0237-0.03860.03430.04290.0287-0.03150.10450.35850.0181-0.12570.15010.13510.1829-35.4374106.459-19.2917
20.1501-0.0491-0.04630.0224-0.00030.04880.1002-0.06820.07330.0065-0.00580.03330.04090.00150.10870.3291-0.0575-0.05240.018-0.04870.1493-35.2902102.0361-2.4727
30.01140.0002-0.01460.07040.02450.0697-0.0253-0.0081-0.00650.0098-0.0678-0.01550.0352-0.0219-0.31020.2833-0.0876-0.13970.00270.1170.1669-36.559494.7075-4.7049
40.0242-0.022-0.00780.0253-0.00250.0186-0.0515-0.0212-0.05020.0146-0.0028-0.01380.02180.0155-0.04440.4148-0.2021-0.06170.23720.17420.2738-39.596286.84195.5289
50.0426-0.0488-0.01310.05870.00990.0411-0.1096-0.0485-0.09040.1438-0.03450.00990.0801-0.0149-0.25510.4622-0.22520.04320.44840.22220.2348-42.600791.198312.1303
60.022-0.01890.0250.0556-0.01450.03840.0606-0.10130.07470.06180.00590.15-0.0649-0.13870.10860.139-0.01360.0760.3083-0.10470.309-52.7027104.53610.1786
7-0.00030.00170.00180.03360.01990.01080.0184-0.05690.1258-0.0011-0.00070.0718-0.0639-0.03750.03890.27870.07940.00590.08-0.08490.3204-42.8414117.62291.1797
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 162 through 193 )
2X-RAY DIFFRACTION2chain 'A' and (resid 194 through 262 )
3X-RAY DIFFRACTION3chain 'A' and (resid 263 through 320 )
4X-RAY DIFFRACTION4chain 'A' and (resid 321 through 356 )
5X-RAY DIFFRACTION5chain 'A' and (resid 357 through 448 )
6X-RAY DIFFRACTION6chain 'A' and (resid 449 through 528 )
7X-RAY DIFFRACTION7chain 'A' and (resid 529 through 565 )

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