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- PDB-7l0k: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 7l0k
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM784 (3-(1-(3-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrole-2-carboxamido)ethyl)-1H-pyrazole-5-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-XE7 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 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 11, 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)92,8378
Polymers90,7722
Non-polymers2,0666
Water5,693316
1
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4194
Polymers45,3861
Non-polymers1,0333
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4194
Polymers45,3861
Non-polymers1,0333
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.117, 158.335, 62.767
Angle α, β, γ (deg.)90.000, 107.278, 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-XE7 / 3-{(1R)-1-[(3-methyl-4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrrole-2-carbonyl)amino]ethyl}-1H-pyrazole-5-carboxamide


Mass: 420.388 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19F3N6O2 / 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.: 316 / 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: 2.67 Å3/Da / Density % sol: 53.9 % / Description: prism
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.8 / Details: PEG4000 v/v 24%, 100 mM Tris-HCl, pH 8.8

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Data collection

DiffractionMean temperature: 100 K / 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: 1.96→36.21 Å / Num. obs: 68810 / % possible obs: 98.9 % / Redundancy: 3.8 % / Biso Wilson estimate: 24.55 Å2 / CC1/2: 0.99 / Rpim(I) all: 0.044 / Net I/σ(I): 12.23
Reflection shellResolution: 1.96→2 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 3388 / CC1/2: 0.503 / Rpim(I) all: 0.604 / % possible all: 99.4

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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: 1.96→36.21 Å / SU ML: 0.213 / Cross valid method: FREE R-VALUE / σ(F): 1.49 / Phase error: 22.6982
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2134 1016 1.7 %
Rwork0.1788 58731 -
obs0.1794 59747 85.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.75 Å2
Refinement stepCycle: LAST / Resolution: 1.96→36.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5965 0 144 316 6425
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00736313
X-RAY DIFFRACTIONf_angle_d0.98698533
X-RAY DIFFRACTIONf_chiral_restr0.0494931
X-RAY DIFFRACTIONf_plane_restr0.00551081
X-RAY DIFFRACTIONf_dihedral_angle_d19.29992345
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.96-2.060.2738690.23054029X-RAY DIFFRACTION41.41
2.06-2.190.22971180.19746766X-RAY DIFFRACTION69.42
2.19-2.360.21321580.18529137X-RAY DIFFRACTION93.47
2.36-2.60.2281680.18299719X-RAY DIFFRACTION99.41
2.6-2.970.21881660.18279595X-RAY DIFFRACTION98.1
2.97-3.740.22241680.17799752X-RAY DIFFRACTION99.51
3.74-36.210.19061690.16739733X-RAY DIFFRACTION98.86
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)
11.984797293830.03421955585231.059819110313.33336127334-1.409080410532.039401012980.419599076796-0.263209923736-0.7080144998340.222776665211-0.0951266969853-0.3291617489360.6836802375310.253925030492-0.168445929490.5040487467750.00733520283861-0.1506556593380.2607223381010.07028706694420.4546213153054.4408879785-55.82443004770.621228148528
21.89464831080.4149646883640.5684430489422.04028257403-0.4221662709040.6760553487330.2692272121-0.308420736648-0.2927839190530.313519839892-0.0653834706496-0.04949210791770.357825420471-0.0804302566435-0.06248982515910.229646942329-0.04064061460510.00177330298280.1632222643480.04457973820620.161083961038-1.25681153476-40.7492029752-2.52993951701
32.57986812853-0.4837646197521.446634058663.721865740370.07798473388152.50214851574-0.0614758841278-0.141779394187-0.0210265955290.0383603820582-0.01081996609420.00673004772421-0.253508300452-0.03387213790180.07063141928510.176186995704-0.01276585435990.05809090186150.1597398373430.01187485229380.088561217471.68016816526-27.4164633775-6.37793235823
42.027897361-0.2492466057020.6556739270892.427238385460.06896769813351.96419616070.1747870170040.03366287839280.443144290178-0.2083321629450.0924168402169-0.389301963104-0.2956760877660.434665174857-0.006567301263460.255669924386-0.02078685791240.09373314977480.217500303907-0.01743819820420.1861913311122.47096327807-27.7950984992-14.3170153815
51.62340745668-0.1935075951250.8994739256572.21910997989-0.36427362032.150694985480.101853795024-0.372754600815-0.2316686220130.2832356263880.08228414783370.4300561170070.164122774074-0.579187645157-0.1145557139450.193706069997-0.0537322025740.06750352147350.3076935939930.04934744257480.191561432597-15.7640924942-38.5374906805-5.37735482895
60.778104721855-0.651579402846-0.6195276440792.27759114043-0.1382341415031.364936150250.1660854691670.219505320344-0.598874459621-0.3732748029880.02543136124360.2550647207870.701703767437-0.673961837856-0.07387200316320.508015686952-0.0977089730426-0.1322743446620.142055297822-0.01418826102980.395673474686-12.2317949807-52.3182701966-17.2300266244
72.101208127480.706725428660.3563473925494.49852159261.188379543043.60570981358-0.267729342297-0.4180497185020.5728596010520.4484244271890.0437048779815-0.0275950565011-0.9367402712160.07853328905420.1753652491340.547246001521-0.000433016257752-0.1235488605330.271025682555-0.0644919312460.37094242338615.46982456897.2383160540134.0029050151
80.6808313505340.05470070823880.3305048198532.87855244668-0.6712558058093.56387672878-0.110537839731-0.1435114255850.1707431461610.225655511855-0.0492720227031-0.0959046723217-0.3938222546170.08162151535870.06708388852980.1460569614250.0121485191857-0.02470909060520.166148735755-0.002781729173580.18674810167812.9296707479-9.5999563646629.0637204266
90.59436614815-0.5854383884061.316095447854.599887746170.6105572119884.56146671160.1035403394410.145504743990.153875578817-0.2081685286360.0243256634904-0.5887951201360.346667672140.657903671941-0.07374995762010.1495558942740.03038807658920.007697295177360.2368170070340.02795429122990.22750929798114.3731740728-24.795902329723.6809174836
101.72229313986-0.3807893250850.5459005665362.575106814410.0930440350012.74922503303-0.08930274682310.2119562756230.200416618393-0.21724076572-0.0399223484399-0.325280053793-0.2263570164260.4398009622470.01262515240520.119953417316-0.0338383882488-0.01182191197670.2424442006210.06503653561850.19322320422318.1865217189-11.802315156214.3774443048
110.954285361796-0.515118806663-0.04960429876712.33269665328-0.4337428924571.15311105983-0.2346269275280.2583346551160.408293712025-0.366194408855-0.02114689003130.0206410902798-0.8303980404870.1903365441950.1580982134630.50052964108-0.0368673858046-0.1169369288060.2061741569010.0846662607130.3919329078810.52259523634.680702614512.7183818639
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid -1 through 205 )AA-1 - 2051 - 49
22chain 'A' and (resid 206 through 282 )AA206 - 28250 - 128
33chain 'A' and (resid 283 through 376 )AA283 - 376129 - 225
44chain 'A' and (resid 377 through 435 )AA377 - 435226 - 254
55chain 'A' and (resid 436 through 534 )AA436 - 534255 - 353
66chain 'A' and (resid 535 through 567 )AA535 - 567354 - 386
77chain 'B' and (resid 159 through 205 )BE159 - 2051 - 47
88chain 'B' and (resid 206 through 320 )BE206 - 32048 - 164
99chain 'B' and (resid 321 through 375 )BE321 - 375165 - 219
1010chain 'B' and (resid 376 through 528 )BE376 - 528220 - 335
1111chain 'B' and (resid 529 through 566 )BE529 - 566336 - 376

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