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- PDB-9dik: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 9dik
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM681 (N-cyclopropyl-1,4-dimethyl-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-3-carboxamide)
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/INHIBITOR / inhibitor / Alpha-Beta Barrel / OXIDOREDUCTASE / Flavoprotein / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


Pyrimidine biosynthesis / pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase (quinone) activity / 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-type TIM barrel
Similarity search - Domain/homology
: / FLAVIN MONONUCLEOTIDE / Chem-OG6 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsDeng, X. / Tomchick, D. / Phillips, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI103947 United States
Citation
Journal: J.Med.Chem. / Year: 2025
Title: Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.
Authors: Nie, Z. / Bonnert, R. / Tsien, J. / Deng, X. / Higgs, C. / El Mazouni, F. / Zhang, X. / Li, R. / Ho, N. / Feher, V. / Paulsen, J. / Shackleford, D.M. / Katneni, K. / Chen, G. / Ng, A.C.F. / ...Authors: Nie, Z. / Bonnert, R. / Tsien, J. / Deng, X. / Higgs, C. / El Mazouni, F. / Zhang, X. / Li, R. / Ho, N. / Feher, V. / Paulsen, J. / Shackleford, D.M. / Katneni, K. / Chen, G. / Ng, A.C.F. / McInerney, M. / Wang, W. / Saunders, J. / Collins, D. / Yan, D. / Li, P. / Campbell, M. / Patil, R. / Ghoshal, A. / Mondal, P. / Kundu, A. / Chittimalla, R. / Mahadeva, M. / Kokkonda, S. / White, J. / Das, R. / Mukherjee, P. / Angulo-Barturen, I. / Jimenez-Diaz, M.B. / Malmstrom, R. / Lawrenz, M. / Rodriguez-Granillo, A. / Rathod, P.K. / Tomchick, D.R. / Palmer, M.J. / Laleu, B. / Qin, T. / Charman, S.A. / Phillips, M.A.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionSep 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jan 29, 2025Group: Structure summary / Category: audit_author / Item: _audit_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
B: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,72310
Polymers90,7722
Non-polymers1,9528
Water4,594255
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A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3394
Polymers45,3861
Non-polymers9533
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3856
Polymers45,3861
Non-polymers9995
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.539, 107.979, 157.835
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 45385.914 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PFF0160c / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): DE3
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 5 types, 263 molecules

#2: Chemical ChemComp-A1A52 / N-cyclopropyl-1,4-dimethyl-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide


Mass: 338.328 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H17F3N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21N4O9P
#4: Chemical ChemComp-OG6 / 6-[bis(oxidanyl)methyl]-5~{H}-pyrimidine-2,4-dione / 6-Formyl-uracil hydrate


Mass: 158.112 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H6N2O4
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 3.22 Å3/Da / Density % sol: 61.77 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.1
Details: 0.12 M Ammonium Acetate, 23% PEG4000, 0.1 M Sodium citrate, pH 6.1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97927 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Nov 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97927 Å / Relative weight: 1
ReflectionResolution: 2.01→500 Å / Num. obs: 79606 / % possible obs: 96.8 % / Redundancy: 5.6 % / Biso Wilson estimate: 24.7 Å2 / CC1/2: 0.978 / Net I/σ(I): 11.13
Reflection shellResolution: 2.01→2.04 Å / Num. unique obs: 3211 / CC1/2: 0.463

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
HKL-3000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→40.96 Å / SU ML: 0.1911 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.7505
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2098 1672 3 %
Rwork0.176 54075 -
obs0.177 55747 80.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.96 Å2
Refinement stepCycle: LAST / Resolution: 2.1→40.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5882 0 134 255 6271
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00886144
X-RAY DIFFRACTIONf_angle_d0.70268296
X-RAY DIFFRACTIONf_chiral_restr0.0511918
X-RAY DIFFRACTIONf_plane_restr0.00591049
X-RAY DIFFRACTIONf_dihedral_angle_d14.51022299
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.160.279690.2242255X-RAY DIFFRACTION40.82
2.16-2.230.2578850.21622732X-RAY DIFFRACTION49.8
2.23-2.310.24311010.19863273X-RAY DIFFRACTION59.27
2.31-2.40.27111150.19773711X-RAY DIFFRACTION67.24
2.4-2.510.2041290.19034173X-RAY DIFFRACTION75.13
2.51-2.650.22441440.19794668X-RAY DIFFRACTION84.21
2.65-2.810.21691590.19585161X-RAY DIFFRACTION93.24
2.81-3.030.22061720.19285543X-RAY DIFFRACTION99.55
3.03-3.330.21321720.18015589X-RAY DIFFRACTION99.86
3.33-3.820.19531730.16635596X-RAY DIFFRACTION99.45
3.82-4.810.18771740.14695610X-RAY DIFFRACTION98.92
4.81-40.960.1991790.16645764X-RAY DIFFRACTION97.67
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)
11.641421347060.193143484931.544148702162.35184592041-2.047241362674.28902167545-0.00679167885998-0.902672796950.05636786522960.646100959158-0.1341747914380.4157559513360.096704113535-0.09829096108250.1042501566980.5369776968210.01752011726430.2185602580960.6302665957760.0223810562810.3076381645820.82135870423312.955350080928.2680707221
20.6961407956140.4687061876470.574880586281.78321477803-0.1304529662751.07074391150.0458528829862-0.6326363074180.4188291181520.639608415372-0.1269796334840.0571004776078-0.03413781695370.1195956638950.09363375656990.373706442527-0.004603092272-0.02423598323650.470752409979-0.08111171397920.16999875348116.22173033223.044916314922.3512004416
31.27218119660.2424533620890.2201544321382.531668634350.1596172095441.69199779491-0.0725333175273-0.443021299534-0.05779941853050.4046207307160.09423020095920.51423421293-0.0148521197736-0.04938747849210.06914389299010.1744163644340.04112159641010.07246678048490.2506424781610.003187317057070.1817731959133.9640452648916.883824291912.7544646394
42.86926557722-1.103643071431.429050245024.393553481020.6144752812777.45830012478-0.184468068174-0.4533350699430.4026478269830.4340273759580.1666280744850.255972905152-0.642889544352-0.04425498292020.392016560160.336041402037-0.002405860499070.1140158886310.272232757084-0.2403227225760.3352726069756.7785288767535.545838986916.8290379588
53.180615044790.2802026851610.4362224870263.68164253455-0.5497145980323.84345948717-0.07622488289370.003439389701540.118208553839-0.1071473679110.0956682362910.1952858550430.155348381694-0.0304207056216-0.0009001940495670.0874610124662-0.01105003824220.02541090726970.132677619351-0.02298054808660.20061616220810.510162092526.06945749454.06124148973
63.00649129087-0.843109588939-0.7331932951411.934626289373.292315941797.584835103110.05986052964090.2549436785610.753111029949-0.415407205038-0.0524984736024-0.152704392094-0.7408353512150.125067150102-0.03233457208180.211590173663-0.0339269060913-0.01935486446030.1466580289980.03865461383810.34419358244318.336197778431.9136232062-3.57047549942
72.639268117150.960945939579-0.6927671738522.75982811544-0.04707296437081.80510286036-0.188116068057-0.135218494873-0.122381574107-0.1119500327150.105933208072-0.01202054982090.07656635639720.1220833377510.07666376918590.1039343813840.0338771006037-0.03414540391440.1125455564970.00743843771960.12312679109216.799618209216.39979213273.55092564045
82.051316529660.785272895378-0.3492877399071.96082087498-0.2444449291951.59338786285-0.0496951793612-0.566995848901-0.3905923660730.3509849223570.00586317994107-0.3363338517130.1032499445550.2038590924730.06000676277430.1848594324440.0456919918138-0.03651609136940.1986362965380.03768987896950.1700140386721.14895015210.032404411811.9326830657
91.56016167109-0.1464987589650.1489841685481.448256104540.1268401508531.443014393920.123002035955-0.401458287488-0.2196673620820.6530155845190.00816630858215-0.3690886841190.1542422518450.2675135367160.1917374720250.4551293844290.064484575427-0.168926714710.6641825065820.0974158657590.18140494483927.154559274311.74237420324.3613344992
102.56489958118-0.353833921938-0.1795304909362.05541403388-0.0652116322731.846088620280.0715899933010.996947290459-0.00554064512387-0.663231350683-0.04160475843560.38816148092-0.138023567484-0.163753484318-0.03457250083770.389131203452-0.00680926623277-0.0600756106220.5066526514650.01245078678430.2821304944983.29047765796-16.2584288716-23.8515876045
112.756973584360.113834321333-0.2313570314372.42322281658-0.5332377849681.82047349394-0.04874151786060.339958697778-0.0404891546665-0.1102491173830.1172878499110.324389346870.0785464175327-0.0432191089613-0.03881907932040.124542371168-0.0165731893589-0.0279243341450.171557385658-0.03417350413840.2727735661721.89232782162-23.2091884591-9.14634534566
121.776482543080.634959457231.191988431814.59073600341.990399928397.047875271520.08421163899260.103729758105-0.7031162794650.3933369317930.0521405285245-0.1237671225691.059681593430.0337035618874-0.1325903790550.197106429155-0.005513925135940.02559647641650.193543063253-0.04324211329010.43217376689112.3863347321-33.9863201948-0.72100965832
132.59169132234-0.7874702786890.1664671227191.871319972630.07578253821892.26509699392-0.1439486493190.01574301595150.3934874927060.1271254803790.1380183034780.0937220629688-0.3332388459410.02566609140310.02639437866460.143515678135-0.0208950632520.03915922875710.126229992256-0.001271936281540.30486133268712.4835544687-11.5254340876-2.6257617082
142.49449034346-0.0748156812781-0.1910198428392.05060921048-0.2690492934752.591994934570.007204183285410.7874568765260.388053192167-0.4911932313060.109764329894-0.28271196412-0.2776303392340.241777153231-0.09220629737250.29899625819-0.03771378346730.08142382621120.3016458520030.07735870020390.275725957918.4247874378-10.2478671986-18.1173522283
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 159 through 193 )AA159 - 1931 - 35
22chain 'A' and (resid 194 through 233 )AA194 - 23336 - 75
33chain 'A' and (resid 234 through 282 )AA234 - 28276 - 124
44chain 'A' and (resid 283 through 299 )AA283 - 299125 - 141
55chain 'A' and (resid 300 through 356 )AA300 - 356142 - 198
66chain 'A' and (resid 357 through 377 )AA357 - 377199 - 219
77chain 'A' and (resid 378 through 474 )AA378 - 474220 - 280
88chain 'A' and (resid 475 through 534 )AA475 - 534281 - 340
99chain 'A' and (resid 535 through 566 )AA535 - 566341 - 372
1010chain 'B' and (resid 161 through 233 )BE161 - 2331 - 73
1111chain 'B' and (resid 234 through 356 )BE234 - 35674 - 196
1212chain 'B' and (resid 357 through 418 )BE357 - 418197 - 222
1313chain 'B' and (resid 419 through 495 )BE419 - 495223 - 299
1414chain 'B' and (resid 496 through 566 )BE496 - 566300 - 370

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