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- PDB-7l01: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 7l01
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM782 (N-(1-(5-cyano-1H-pyrazol-3-yl)ethyl)-3-methyl-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-XCV / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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)92,8548
Polymers90,7722
Non-polymers2,0826
Water11,097616
1
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4274
Polymers45,3861
Non-polymers1,0413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4274
Polymers45,3861
Non-polymers1,0413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.059, 158.027, 61.050
Angle α, β, γ (deg.)90.000, 104.600, 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-XCV / N-[(1R)-1-(5-cyano-1H-pyrazol-3-yl)ethyl]-3-methyl-4-{1-[6-(trifluoromethyl)pyridin-3-yl]cyclopropyl}-1H-pyrrole-2-carboxamide


Mass: 428.410 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H19F3N6O / 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.: 616 / 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: 2.52 Å3/Da / Density % sol: 51.2 % / 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 / 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: 1.6→33.39 Å / Num. obs: 114807 / % possible obs: 95.9 % / Redundancy: 3.6 % / Biso Wilson estimate: 13.76 Å2 / CC1/2: 0.99 / Rpim(I) all: 0.048 / Net I/σ(I): 17.24
Reflection shellResolution: 1.6→1.63 Å / Mean I/σ(I) obs: 1.1 / Num. unique obs: 5062 / Rpim(I) all: 0.489 / % possible all: 85.4

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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: 1.6→33.39 Å / SU ML: 0.1229 / Cross valid method: FREE R-VALUE / σ(F): 1.48 / Phase error: 20.3642
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1884 1260 1.3 %
Rwork0.1636 95622 -
obs0.1639 96882 80.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.27 Å2
Refinement stepCycle: LAST / Resolution: 1.6→33.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6007 0 146 616 6769
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0116299
X-RAY DIFFRACTIONf_angle_d1.11578511
X-RAY DIFFRACTIONf_chiral_restr0.0569935
X-RAY DIFFRACTIONf_plane_restr0.00741079
X-RAY DIFFRACTIONf_dihedral_angle_d17.99792355
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.660.2754520.20583951X-RAY DIFFRACTION29.99
1.66-1.740.2091820.20566170X-RAY DIFFRACTION46.99
1.74-1.830.2291170.20279006X-RAY DIFFRACTION68.45
1.83-1.950.2071620.18512236X-RAY DIFFRACTION92.85
1.95-2.10.18811690.163512819X-RAY DIFFRACTION96.87
2.1-2.310.18421660.149812583X-RAY DIFFRACTION95.95
2.31-2.640.19921710.15613012X-RAY DIFFRACTION98.22
2.64-3.330.1811700.158412886X-RAY DIFFRACTION97.48
3.33-33.390.17291710.159412959X-RAY DIFFRACTION97.51
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)
10.925839369545-0.0386268902310.2639886363251.11342328276-0.1861880582970.874854629496-0.0559769325781-0.02178216837580.164975323698-0.00323802760182-0.02172718416670.0565530086019-0.21925125713-0.03007660902010.02118020098980.328303482308-0.020550816791-0.1001878435210.140645940268-0.05289479584570.220567686479-0.17180175292355.09375106154.367517304
20.53775652168-0.05621547747860.1040485292660.73238343733-0.2206548914660.81724062199-0.0741858270216-0.03925764943450.0925529125936-0.0549433392511-0.03942006520190.0516737545409-0.1410630330110.03269614156810.06367655506410.09472502812770.010299879494-0.01049890846610.0527448855203-0.003351944857360.0891055593178-6.1623171511940.7022781393-3.69458213489
30.9036643085680.101662863082-0.0594998811050.85158678229-0.3340099271420.82183620517-0.0628645498863-0.04933560793030.02105844964690.0565294936546-0.0413501017822-0.0340469965507-0.1627763380090.06089459062750.04780650786940.0955594049594-0.006451988736430.01382199817370.141807118864-0.01853367562210.0644817332501-1.3858971169338.86744969692.39644125714
40.75721659933-0.02892623056070.01124876123750.747739418146-0.09177953333310.723733960096-0.00917109845852-0.0150334744634-0.0103665182681-0.02313714163560.0276721950955-0.05097231949570.03556494367770.0527390652441-0.002689390418690.03820650640390.009555771408190.0262651326780.087005955788-0.001874463864350.0604598603653-3.8989189091228.0426751031-2.97772082768
52.84141907471-0.654225241476-1.206597207862.243739742770.3572844021983.17051095946-0.0474514214347-0.00240871723196-0.2259060197580.08853123142450.02980024764760.133609453110.193869669597-0.1126047039090.05126223877930.137421219857-0.0310044633722-0.003412170690950.1170000920040.002856946183530.0911637441205-9.1623607614418.9167441727-9.43268980605
60.93868685915-0.137048706504-0.1406887786760.7265058556890.246592810660.676830016928-0.04141174919560.039135987981-0.0769930576385-0.01175605025580.02123692709470.02272711338920.02879196098460.02827546347120.03177285346110.0446856757441-0.01743420725380.02909102664440.123632445021-0.002350444254660.0582671194103-6.6025986903927.8671071464-13.5793984846
71.943481397240.5710831866390.7293605880020.5089230325420.3691091026790.571322670119-0.03597826927440.05262001898610.0513698068071-0.0265775177420.0234373992592-0.205965711115-0.1185307377130.200876523802-0.0244819156250.0815679409766-0.06907758473110.01817847940970.1896397695320.01593302762240.15592466922510.795463334137.6592075466-11.8913018622
80.09738620451050.04210540037370.0976438914620.0766358182690.01287632162180.113219388956-0.07054388451510.07584557048150.0241418659684-0.04998893862160.00958195583894-0.0709979954016-0.09671384167160.105754495846-0.04920360115230.143399802414-0.0982799064373-0.007123464091860.1440093252620.04156507389070.08615142873930.064798808512941.0615397622-19.2255261437
90.125792341749-0.02689632273010.131103945060.172802471272-0.06316001402940.302723966921-0.01679445349830.0493589525840.0669551322404-0.09507236345420.01609001225020.065108145466-0.0800441909526-0.01930598484190.03092275282980.346856405846-0.0459156532447-0.1185664659910.1236612018820.06213298422120.229847907994-6.4981920837352.4652889327-17.3526311788
100.476007670663-0.06173323785360.2364479529670.7760056210990.09869556106081.206178318760.04924071151970.00363798528578-0.21145814540.0116083728042-0.00127016787589-0.02863246716360.1820526687910.0353371505839-0.01486146625160.3604507408960.0348400751396-0.1524171674080.1733844389950.01837754157810.32124477696220.2814735638-8.1234229197229.6375725971
110.7001655127210.05768813776630.3095187941180.6932723089460.1200880151730.5700922310590.08848681968650.00460202157673-0.08937133702080.06628267473410.0233582746242-0.1041979803590.0372509180560.0609954337244-0.06768657872110.0664255907477-0.002144156335170.01716909483930.067363391297-0.01374100724240.061380886740516.172848060815.742381075223.4978920809
120.426157893453-0.06204511417820.2435463415360.524239391218-0.08349467339920.4118263470960.0888944230559-0.148610085954-0.1345007618320.1281654304260.02827281321920.1065709486190.0890257649145-0.184518401227-0.01921056435570.0954990505528-0.04734318780520.01752030952740.1173113188540.0448305719210.0933854126105-0.79955329978510.151913979123.8369277247
130.2345083494030.07709755445470.1942894091360.3672269414030.1499252512660.4992178036270.006022600917510.0358071604289-0.0915839935307-0.0470380916308-0.01308205153550.05201019941670.0701643039384-0.0297083865018-0.0350725059880.273324908139-0.0310822214963-0.1061724024150.0949609625673-0.02077413677030.2508945389874.74705776811-4.0388488756215.1653289427
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 203 )AA159 - 2031 - 45
22chain 'A' and (resid 204 through 262 )AA204 - 26246 - 106
33chain 'A' and (resid 263 through 299 )AA263 - 299107 - 143
44chain 'A' and (resid 300 through 356 )AA300 - 356144 - 205
55chain 'A' and (resid 357 through 376 )AA357 - 376206 - 225
66chain 'A' and (resid 377 through 449 )AA377 - 449226 - 262
77chain 'A' and (resid 450 through 474 )AA450 - 474263 - 287
88chain 'A' and (resid 475 through 528 )AA475 - 528288 - 341
99chain 'A' and (resid 529 through 566 )AA529 - 566342 - 379
1010chain 'B' and (resid -7 through 205 )BE-7 - 2051 - 53
1111chain 'B' and (resid 206 through 435 )BE206 - 43554 - 255
1212chain 'B' and (resid 436 through 528 )BE436 - 528256 - 351
1313chain 'B' and (resid 529 through 567 )BE529 - 567352 - 390

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