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- PDB-6r8g: Crystal structure of malate dehydrogenase from Plasmodium Falcipa... -

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Basic information

Entry
Database: PDB / ID: 6r8g
TitleCrystal structure of malate dehydrogenase from Plasmodium Falciparum in complex with 4-(3,4-difluorophenyl)thiazol-2-amine
ComponentsMalate dehydrogenase
KeywordsOXIDOREDUCTASE
Function / homology
Function and homology information


carboxylic acid metabolic process / L-lactate dehydrogenase activity
Similarity search - Function
Malate dehydrogenase, type 3 / L-2-Hydroxyisocaproate Dehydrogenase; Chain A, domain 2 / Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal / L-lactate/malate dehydrogenase / Lactate/malate dehydrogenase, N-terminal / Lactate/malate dehydrogenase, C-terminal / lactate/malate dehydrogenase, NAD binding domain / lactate/malate dehydrogenase, alpha/beta C-terminal domain / Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal / NAD(P)-binding Rossmann-like Domain ...Malate dehydrogenase, type 3 / L-2-Hydroxyisocaproate Dehydrogenase; Chain A, domain 2 / Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal / L-lactate/malate dehydrogenase / Lactate/malate dehydrogenase, N-terminal / Lactate/malate dehydrogenase, C-terminal / lactate/malate dehydrogenase, NAD binding domain / lactate/malate dehydrogenase, alpha/beta C-terminal domain / Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Alpha-Beta Complex / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
4-[3,4-bis(fluoranyl)phenyl]-1,3-thiazol-2-amine / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / L-lactate dehydrogenase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsRomero, A.R. / Calderone, V. / Gentili, M. / Lunev, S. / Groves, M. / Popowicz, G. / Domling, A. / Sattler, M.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
European Union675555 Netherlands
Citation
Journal: Commun Biol / Year: 2021
Title: A Fragment-Based Approach Identifies an Allosteric Pocket that Impacts Malate Dehydrogenase Activity
Authors: Romero, A.R. / Lunev, S. / Popowicz, G. / Calderone, V. / Gentili, M. / Sattler, M. / Plewka, J. / Taube, M. / Kozak, M. / Holak, T.A. / Domling, A. / Groves, M.
#1: Journal: PLoS ONE / Year: 2018
Title: Oligomeric interfaces as a tool in drug discovery: Specific interference with activity of malate dehydrogenase of Plasmodium falciparum in vitro.
Authors: Lunev, S. / Butzloff, S. / Romero, A.R. / Linzke, M. / Batista, F.A. / Meissner, K.A. / Muller, I.B. / Adawy, A. / Wrenger, C. / Groves, M.R.
History
DepositionApr 1, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 4, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Malate dehydrogenase
B: Malate dehydrogenase
C: Malate dehydrogenase
D: Malate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,98710
Polymers141,4524
Non-polymers1,5356
Water4,774265
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15670 Å2
ΔGint-87 kcal/mol
Surface area43480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.760, 106.890, 145.010
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: THR / Beg label comp-ID: THR / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEUAA2 - 3112 - 311
21LEULEUBB2 - 3112 - 311
12LEULEUAA2 - 3112 - 311
22LEULEUCC2 - 3112 - 311
13ILEILEAA2 - 3122 - 312
23ILEILEDD2 - 3122 - 312
14LYSLYSBB2 - 3132 - 313
24LYSLYSCC2 - 3132 - 313
15LEULEUBB2 - 3112 - 311
25LEULEUDD2 - 3112 - 311
16LEULEUCC2 - 3112 - 311
26LEULEUDD2 - 3112 - 311

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Malate dehydrogenase


Mass: 35362.922 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: Four molecules of 4-(3,4-difluorophenyl)thiazol-2-amine were modeled at the oligomeric interface
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Plasmid: pETM-13 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q6VVP7, malate dehydrogenase
#2: Chemical
ChemComp-JUT / 4-[3,4-bis(fluoranyl)phenyl]-1,3-thiazol-2-amine


Mass: 212.219 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H6F2N2S
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 265 / Source method: isolated from a natural source / Formula: H2O

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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: 2.32 Å3/Da / Density % sol: 47.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 1.4 M trisodium citrate, 0.1 M Hepes

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: BRUKER D8 QUEST / Wavelength: 1.54 Å
DetectorType: Bruker PHOTON II / Detector: PIXEL / Date: Mar 15, 2019
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 89246 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 14.1 % / Rsym value: 0.2 / Net I/σ(I): 21.1
Reflection shellResolution: 2→2.12 Å / Num. unique obs: 14220

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5nfr

5nfr


Resolution: 2→48.97 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.936 / SU B: 11.621 / SU ML: 0.144 / Cross valid method: THROUGHOUT / ESU R: 0.199 / ESU R Free: 0.166 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23846 4463 5 %RANDOM
Rwork0.21025 ---
obs0.21167 84786 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 33.266 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å20 Å20 Å2
2--0.31 Å2-0 Å2
3----0.25 Å2
Refinement stepCycle: 1 / Resolution: 2→48.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9482 0 101 265 9848
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0139722
X-RAY DIFFRACTIONr_bond_other_d0.0360.0179337
X-RAY DIFFRACTIONr_angle_refined_deg1.8851.63513147
X-RAY DIFFRACTIONr_angle_other_deg2.3581.57621742
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.51651242
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.41725.149404
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.059151784
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5121524
X-RAY DIFFRACTIONr_chiral_restr0.090.21348
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0210707
X-RAY DIFFRACTIONr_gen_planes_other0.0140.021733
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.952.5144980
X-RAY DIFFRACTIONr_mcbond_other1.952.5144979
X-RAY DIFFRACTIONr_mcangle_it3.053.7656218
X-RAY DIFFRACTIONr_mcangle_other3.053.7656219
X-RAY DIFFRACTIONr_scbond_it2.3962.8344742
X-RAY DIFFRACTIONr_scbond_other2.3962.8354743
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.7824.126930
X-RAY DIFFRACTIONr_long_range_B_refined11.37130.7310647
X-RAY DIFFRACTIONr_long_range_B_other11.36430.65710611
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A96120.1
12B96120.1
21A94470.12
22C94470.12
31A95020.12
32D95020.12
41B95130.11
42C95130.11
51B94700.11
52D94700.11
61C97130.09
62D97130.09
LS refinement shellResolution: 2.001→2.053 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 323 -
Rwork0.327 6140 -
obs--99.14 %
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)
11.17830.07310.53260.81060.12961.0482-0.05810.2639-0.0566-0.11940.0599-0.1074-0.09530.2762-0.00190.0775-0.02610.04270.1509-0.00660.031839.785345.6237-34.6882
21.057-0.20590.17240.6761-0.02340.8605-0.0892-0.10250.16960.03480.03080.0053-0.2179-0.1150.05840.11720.0663-0.02170.0409-0.02080.03216.690664.0151-12.8557
30.7286-0.09350.15560.5359-0.22110.6962-0.0862-0.09160.06630.07120.0039-0.0926-0.16090.03890.08230.04620.0043-0.03060.0322-0.01720.03435.528551.71562.1841
40.46510.0895-0.02320.6953-0.2340.6006-0.02260.0174-0.0592-0.09640.05440.01890.0389-0.0558-0.03180.0255-0.01610.00110.0308-0.00830.014510.77328.8607-25.0564
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 400
2X-RAY DIFFRACTION2B2 - 400
3X-RAY DIFFRACTION3C2 - 401
4X-RAY DIFFRACTION4D2 - 400

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