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- PDB-7kyk: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 7kyk
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM589 (ethyl 3-methyl-4-((4-(trifluoromethyl)benzo[d]oxazol-7-yl)methyl)-1H-pyrrole-2-carboxylate)
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrialDihydroorotate dehydrogenase (quinone)
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Alpha-Beta Barrel / 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-type TIM barrel
Similarity search - Domain/homology
FLAVIN MONONUCLEOTIDE / OROTIC ACID / Chem-XAJ / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsDeng, X. / Phillips, M. / Tomchick, D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI103947 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.
Authors: Palmer, M.J. / Deng, X. / Watts, S. / Krilov, G. / Gerasyuto, A. / Kokkonda, S. / El Mazouni, F. / White, J. / White, K.L. / Striepen, J. / Bath, J. / Schindler, K.A. / Yeo, T. / ...Authors: Palmer, M.J. / Deng, X. / Watts, S. / Krilov, G. / Gerasyuto, A. / Kokkonda, S. / El Mazouni, F. / White, J. / White, K.L. / Striepen, J. / Bath, J. / Schindler, K.A. / Yeo, T. / Shackleford, D.M. / Mok, S. / Deni, I. / Lawong, A. / Huang, A. / Chen, G. / Wang, W. / Jayaseelan, J. / Katneni, K. / Patil, R. / Saunders, J. / Shahi, S.P. / Chittimalla, R. / Angulo-Barturen, I. / Jimenez-Diaz, M.B. / Wittlin, S. / Tumwebaze, P.K. / Rosenthal, P.J. / Cooper, R.A. / Aguiar, A.C.C. / Guido, R.V.C. / Pereira, D.B. / Mittal, N. / Winzeler, E.A. / Tomchick, D.R. / Laleu, B. / Burrows, J.N. / Rathod, P.K. / Fidock, D.A. / Charman, S.A. / Phillips, M.A.
History
DepositionDec 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
C: Dihydroorotate dehydrogenase (quinone), mitochondrial
D: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)185,40316
Polymers181,5444
Non-polymers3,85912
Water6,035335
1
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3514
Polymers45,3861
Non-polymers9653
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3514
Polymers45,3861
Non-polymers9653
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3514
Polymers45,3861
Non-polymers9653
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3514
Polymers45,3861
Non-polymers9653
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)92.158, 97.542, 186.332
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

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


Mass: 45385.914 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7 / Gene: PFF0160c / Production host: Escherichia coli (E. coli)
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)
#2: Chemical
ChemComp-XAJ / ethyl 3-methyl-4-{[4-(trifluoromethyl)-1,3-benzoxazol-7-yl]methyl}-1H-pyrrole-2-carboxylate


Mass: 352.308 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H15F3N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


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


Mass: 156.096 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C5H4N2O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 335 / Source method: isolated from a natural source / Formula: H2O
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: 2.26 Å3/Da / Density % sol: 48.6 % / Description: rectangle
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.17 M Ammonium acatete, 0.085 M sodium citrate pH 5.6, PEG4000 25.5% v/v, 15% v/v Glycerol

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: liquid N2 vapor / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97926 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 92373 / % possible obs: 99.1 % / Redundancy: 5.7 % / Biso Wilson estimate: 26.09 Å2 / Rpim(I) all: 0.039 / Net I/σ(I): 19.1
Reflection shellResolution: 2.15→2.19 Å / Mean I/σ(I) obs: 1.1 / Num. unique obs: 4445 / Rpim(I) all: 0.668

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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: 3I65

3i65


Resolution: 2.15→43.11 Å / SU ML: 0.1982 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.4982
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2236 2002 2.46 %
Rwork0.1828 79344 -
obs0.1838 81346 87.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.28 Å2
Refinement stepCycle: LAST / Resolution: 2.15→43.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11761 0 268 335 12364
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003512244
X-RAY DIFFRACTIONf_angle_d0.50616518
X-RAY DIFFRACTIONf_chiral_restr0.04231824
X-RAY DIFFRACTIONf_plane_restr0.00282086
X-RAY DIFFRACTIONf_dihedral_angle_d19.43451629
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.20.3067660.242505X-RAY DIFFRACTION39.51
2.2-2.260.3212880.22793507X-RAY DIFFRACTION55.2
2.26-2.330.2733970.23224185X-RAY DIFFRACTION65.54
2.33-2.40.24511410.22295312X-RAY DIFFRACTION83.48
2.4-2.490.27111590.20476042X-RAY DIFFRACTION94.61
2.49-2.590.26031570.20256261X-RAY DIFFRACTION98.3
2.59-2.70.21911520.19936354X-RAY DIFFRACTION98.74
2.7-2.850.22381720.19696307X-RAY DIFFRACTION98.87
2.85-3.020.25041600.19356392X-RAY DIFFRACTION99.71
3.02-3.260.25671560.18096427X-RAY DIFFRACTION99.62
3.26-3.590.20281620.17326419X-RAY DIFFRACTION99.19
3.59-4.10.19611630.16076443X-RAY DIFFRACTION99.44
4.1-5.170.19321620.15336533X-RAY DIFFRACTION99.47
5.17-43.110.20241670.18136657X-RAY DIFFRACTION98.1
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)
12.99847096642-0.6593798962770.08061771797241.47748981178-0.2831863226712.621156362570.2337531056050.204662964525-0.162338951498-0.32876526736-0.07334086031420.3064254663240.171831599755-0.0832096718751-0.1043541401650.273700504458-0.00216593941159-0.07971465794190.194883250313-0.0475722222940.18693608217217.2719502798103.2293541839.51302612176
21.79708918241-0.4160734312360.2996508081561.801246110770.02412861354992.0810966160.212749465625-0.0489045105523-0.317126548734-0.19219672498-0.009380073227180.3023306370310.48956506495-0.0924928532418-0.1436309723420.287624900394-0.0136845444942-0.07961163156230.180810011155-0.0001537332469220.14069179198124.650643848793.203084826121.7029874808
38.129123727760.43784529710.675758148685.481695896762.441046457615.19652481666-0.07725597655630.0478007318783-0.6859601329930.4820090237050.253706638055-0.398438279141.079587140840.782284711041-0.1728983182260.271370834860.0876350314895-0.03079520268580.2756892237620.05389518095820.15777579036841.763710770287.964530383827.3357031864
41.86530764587-0.5163225979210.7168789461131.83383729253-0.5169986976681.841134879060.0155031160346-0.05191133283350.190861256444-0.0342593446814-0.0294522910572-0.0459087690928-0.09405540131150.1208287022220.003338879237140.1467664535670.004696585761120.01149106989680.19022849561-0.02054682094010.090928100277831.5187524526108.76855565221.1986809609
55.271511946394.165941039381.414529716733.484013567431.688208245322.94026391960.02404622508060.9225890927780.00639614061461-0.4238889397940.568258541413-0.842539889431-0.06914681927411.57912749178-0.4756743597460.334983967087-0.02448879661250.1498315605310.623721825174-0.174293228730.7415324168234.7438414597135.0558436367.25650749729
67.966916725962.59197527566.690405374162.36948317141.955605867027.56750881283-0.00833367167176-0.03366063070250.488511839676-0.276070541732-0.126409067836-0.177509598028-0.3608365592210.3039628429180.1478013310740.309251019449-0.02144194473490.1853020230030.289791224562-0.07084033180840.44091335373826.991632232144.3869430937.6469302423
71.59789449348-0.356896478547-0.6124214564641.345318151650.7612551931481.944807960970.0337874660861-0.1495450841280.0840713716961-0.06708283057030.0408188918982-0.140506697049-0.2301296612920.0866005163336-0.04861036861910.1816274417330.005338981596540.0385926816580.183296586025-0.01093649758020.19733677813211.5903586061141.96448102818.7506812757
85.919030927861.86902633147-1.879569043263.03124722378-0.1227115321143.72988816792-0.2190381592741.573236254980.443858103869-0.7590123044550.4252970254030.379846115261-0.0704721854467-0.7016801555570.003449042821080.744709827575-0.00485439606466-0.2429831724160.746751162414-0.009076427712370.55705746547548.3529259493155.9652141219.65571041295
95.898025046331.23861357769-3.133327253172.77072947939-0.0915727377963.564560975380.1591719153820.38234340693-0.407104777513-0.246758746434-0.3116334154750.171158985176-0.0248870299675-0.53695426360.1712054047550.2797181392320.0130091822544-0.06557033760290.327896386937-0.04552307740240.1762001437755.5716040195146.30865616911.8170772558
101.798611168210.0583819047177-0.05909885736742.322823619490.1715572933661.77770165181-0.04502748942030.0164111424889-0.155373562825-0.0618791645005-0.05109718791560.2159024425770.276467940177-0.2077590519360.07101458163070.181265137-0.03803679902790.03353365101820.177637932862-0.03391813115930.13302539562261.6311482164140.801536425.769801966
111.93002473064-0.416453676681-1.524560921831.802829098261.398609197535.2883471848-0.0431987032865-0.167648625839-0.165115225040.330211110069-0.0653337478338-0.1705057274650.389079115632-0.01324967428420.0730031578890.17362768938-0.0007914093765690.004103011196550.1716186251670.01332233819210.11310285106571.7557886772139.92495835737.0994189455
124.19539793415-1.67307051496-0.4682820777892.300140320980.2257947690161.25629126958-0.157259113946-0.308749805419-0.04187293848830.3015295617220.06390599253270.2340012844060.170819974301-0.5318062022670.05406648641620.1094123507690.02480795046460.08072473458190.38587973486-0.05619894318960.11483435790954.687045388153.03117330635.8541024004
132.806915122730.4936150486750.521786059022.32774952826-0.234671102842.07457522707-0.0784698888823-0.03634692160780.32269250226-0.0443708817048-0.00443843875928-0.0448856010571-0.2384030044270.004074462769460.05108802135250.1454177421160.03273796294570.01151383665970.0939921549128-0.03157798253350.12726561003267.3838445597159.75703144226.8067411301
144.725265535250.4035682196520.7142877796781.488534064690.202021749091.275986104850.138896548526-0.4485808229860.2679420340330.408167944028-0.213835869180.7299490997980.0525125582962-0.5643268139170.07581790277770.3178754309070.01539026673470.05600453654690.415164233815-0.08942040106960.63626998007311.3618484154141.87519525780.7658295092
151.72260389910.698754093065-0.3833447585823.837063054470.02779515912141.85443613121-0.1359783175960.3358769938750.134069772951-0.5959117345710.04399997469620.64300495316-0.12084765739-0.2287800835360.05089646641410.2092235453630.0122020163267-0.1882610485050.23306335867-0.005198769317970.29234391980923.1987158773143.62428806862.4361834385
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -2 through 233 )
2X-RAY DIFFRACTION2chain 'A' and (resid 234 through 356 )
3X-RAY DIFFRACTION3chain 'A' and (resid 357 through 377 )
4X-RAY DIFFRACTION4chain 'A' and (resid 378 through 566 )
5X-RAY DIFFRACTION5chain 'B' and (resid 162 through 178 )
6X-RAY DIFFRACTION6chain 'B' and (resid 179 through 205 )
7X-RAY DIFFRACTION7chain 'B' and (resid 206 through 566 )
8X-RAY DIFFRACTION8chain 'C' and (resid 163 through 178 )
9X-RAY DIFFRACTION9chain 'C' and (resid 179 through 205 )
10X-RAY DIFFRACTION10chain 'C' and (resid 206 through 356 )
11X-RAY DIFFRACTION11chain 'C' and (resid 357 through 448 )
12X-RAY DIFFRACTION12chain 'C' and (resid 449 through 474 )
13X-RAY DIFFRACTION13chain 'C' and (resid 475 through 566 )
14X-RAY DIFFRACTION14chain 'D' and (resid 162 through 205 )
15X-RAY DIFFRACTION15chain 'D' and (resid 206 through 566 )

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