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

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Basic information

Entry
Database: PDB / ID: 7kzy
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM778 (3-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)ethyl)-4-(1-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1H-pyrrole-2-carboxamide)
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-XCM / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 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 10, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,8328
Polymers90,7722
Non-polymers2,0606
Water8,503472
1
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4164
Polymers45,3861
Non-polymers1,0303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4164
Polymers45,3861
Non-polymers1,0303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.409, 158.194, 62.574
Angle α, β, γ (deg.)90.000, 106.238, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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


Mass: 45385.914 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7 / Gene: PFF0160c / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): DE3
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)
#2: Chemical ChemComp-XCM / 3-methyl-N-[(1R)-1-(5-methyl-1H-pyrazol-3-yl)ethyl]-4-{1-[6-(trifluoromethyl)pyridin-3-yl]cyclopropyl}-1H-pyrrole-2-carboxamide


Mass: 417.427 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H22F3N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


Mass: 456.344 Da / Num. of mol.: 2 / 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.: 2 / Source method: obtained synthetically / Formula: C5H4N2O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 472 / 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: 2.64 Å3/Da / Density % sol: 53.4 % / Description: prism
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.8
Details: 50 mM MgCl2, PEG4000 v/v 24%, 100 mM Tris-HCl, pH 8.8

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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: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.75→33.03 Å / Num. obs: 90365 / % possible obs: 93.2 % / Redundancy: 3.5 % / Biso Wilson estimate: 19.88 Å2 / Rpim(I) all: 0.059 / Net I/σ(I): 11.64
Reflection shellResolution: 1.75→1.78 Å / Redundancy: 2.9 % / Mean I/σ(I) obs: 1 / Num. unique obs: 3334 / Rpim(I) all: 0.536 / % possible all: 68.2

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3I65

3i65


Resolution: 1.75→33.03 Å / SU ML: 0.1832 / Cross valid method: FREE R-VALUE / σ(F): 1.49 / Phase error: 22.957
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.204 1456 2 %
Rwork0.1652 71335 -
obs0.1659 72791 75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.38 Å2
Refinement stepCycle: LAST / Resolution: 1.75→33.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6055 0 144 472 6671
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01186338
X-RAY DIFFRACTIONf_angle_d1.20268566
X-RAY DIFFRACTIONf_chiral_restr0.0579940
X-RAY DIFFRACTIONf_plane_restr0.00651088
X-RAY DIFFRACTIONf_dihedral_angle_d18.1672368
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.810.2749590.23882925X-RAY DIFFRACTION30.88
1.81-1.880.2509840.20824110X-RAY DIFFRACTION43.41
1.88-1.970.24561070.19365243X-RAY DIFFRACTION55
1.97-2.070.20561270.17916169X-RAY DIFFRACTION65.13
2.07-2.20.21061450.16297093X-RAY DIFFRACTION74.7
2.2-2.370.21181690.16018278X-RAY DIFFRACTION87.02
2.37-2.610.20021880.17079261X-RAY DIFFRACTION97.41
2.61-2.980.21321910.16319373X-RAY DIFFRACTION98.36
2.98-3.760.21511930.16259440X-RAY DIFFRACTION99.3
3.76-33.030.17711930.15679443X-RAY DIFFRACTION98.3
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)
10.3708893805840.0943922863729-0.2472363778890.3881840280340.07553506295571.202119721770.218521964493-0.184521204092-0.5889217184570.1396800378590.035733425429-0.1865101789760.4849738299130.2744441262680.1785590823110.5126340718410.0829882770757-0.2205922624330.1592485311970.02076620422430.44271782807420.71566502-56.588226241529.9928522593
21.123642702840.3415044738190.6695764454411.447061191710.02677449294150.5887117975890.271359205957-0.143344725072-0.1931511263580.258099808556-0.032657109756-0.1390072451510.288167233639-0.0155726048177-0.08259694289470.1851529235470.0129154299463-0.01438813693960.1139350940570.01010953413760.13211473737615.3345467753-40.807078730627.1174100013
31.472899483070.07487112187080.7429664967021.750655437790.1584407336521.560325474270.0373779080006-0.00544763001019-0.006039347622720.0643131562370.03896500865-0.110671773627-0.1696458426330.108377208985-0.0735348112910.1349519853550.02606433881080.04241006846790.134618904524-0.02713747703520.10287912060918.0902552214-27.585137890223.1773636094
40.263652729979-0.1882615423470.2875493793690.8415564487020.03930093158070.7367993296510.08816251907760.1302548515740.233836632557-0.0618980238610.16581836718-0.313388543898-0.3385098322960.239879514253-0.2116057739170.113948865961-0.0110533677720.275155398120.277548068429-0.08785323602120.11984524808418.8973740403-27.982656739915.3235748292
50.933738387597-0.1542383685650.6358409768171.02221482610.1650099189191.080328383130.0974456215798-0.232762391582-0.1411511949970.1752279160790.04792799319590.2598420098270.0757313701813-0.396491102193-0.1276248412950.150273912657-0.001378088510170.04466922526960.2155987246050.04569781118580.1584069840910.145522059537-37.98987639823.6590476226
60.209080786991-0.161674860411-0.01874468863670.666918176755-0.1004886345551.123228650220.1795472489010.05935239747-0.354005445314-0.06194079143480.02590983192830.1188467552380.432489570294-0.2397316799810.02873958159320.384261374542-0.0140234810197-0.1374832362630.0933776927316-0.009523074886750.3227714048315.7457913639-52.530662490515.1420912897
70.6749515244560.0754591907694-0.1036635314630.7524213836750.3338149549710.398739350974-0.310230087043-0.1352632415110.483564880590.1710810011070.0458030872153-0.0441691956152-0.8124323541440.1276192907670.07653780114680.494985410856-0.0299382279107-0.1516099920240.192800045415-0.01236946198040.31455727085131.93707151458.1333271342563.133530318
80.1635892889550.149676394689-0.1252340043521.25851989469-0.3552438417071.4657801807-0.146596836035-0.01145525370440.1327875030550.112697949891-0.0629558453761-0.120649613462-0.331703592180.2411423193710.08310876617830.106223362239-0.0329949794151-0.02306961958760.1375265290220.02640519830410.16689216677732.5895915526-7.4582884077356.8042311524
90.966352758404-0.3351921806770.5997312447311.83855093994-0.03182845696082.130364007160.000720098994898-0.0331933972612-0.0171210218675-0.02755631508940.0537304445169-0.03655041517970.1406829971570.111781354281-0.03709124046290.05855765922060.003497636460440.02177674757430.114067010430.01514530636060.11745269226128.0891619146-20.85703307357.0697106105
101.16617324758-0.3232221138320.4384181481781.214136219090.1219337909151.443720463550.00963783924647-0.0370156843579-0.0156331678998-0.114807764515-0.0726675743003-0.05001084702780.08029695634680.424025287204-0.02207646033970.0521763462727-0.01308162195350.04543594172870.2572199136630.02383004924110.14449144622935.0284888516-16.252092804546.7730712738
110.8441706768480.04871093243410.1995948267771.222148818050.1756854096680.726314226352-0.2077965484060.3846666827930.225265911793-0.285674904927-0.00799372334291-0.0418348973286-0.5657357113420.4286119523710.05765243358730.254012812676-0.0956864608154-0.02734708753310.1960453673380.06963054414770.17678358138131.2183177221-1.8956640758541.4653601467
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid -7 through 205 )AA-7 - 2051 - 53
22chain 'A' and (resid 206 through 282 )AA206 - 28254 - 134
33chain 'A' and (resid 283 through 376 )AA283 - 376135 - 230
44chain 'A' and (resid 377 through 435 )AA377 - 435231 - 259
55chain 'A' and (resid 436 through 528 )AA436 - 528260 - 352
66chain 'A' and (resid 529 through 566 )AA529 - 566353 - 390
77chain 'B' and (resid -7 through 205 )BE-7 - 2051 - 53
88chain 'B' and (resid 206 through 282 )BE206 - 28254 - 132
99chain 'B' and (resid 283 through 376 )BE283 - 376133 - 228
1010chain 'B' and (resid 377 through 474 )BE377 - 474229 - 290
1111chain 'B' and (resid 475 through 566 )BE475 - 566291 - 382

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