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- PDB-4kp7: Structure of Plasmodium IspC in complex with a beta-thia-isostere... -

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Basic information

Entry
Database: PDB / ID: 4kp7
TitleStructure of Plasmodium IspC in complex with a beta-thia-isostere derivative of Fosmidomycin
Components1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast
Keywordsoxidoreductase/oxidoreductase INHIBITOR / DXP pathway / drug optimization / non-covalent inhibition / malaria / tuberculosis / Rossmann fold / Reductoisomerase / NADPH Binding / Apicoplast / oxidoreductase-oxidoreductase INHIBITOR complex
Function / homology
Function and homology information


apicoplast / isopentenyl diphosphate biosynthetic process, methylerythritol 4-phosphate pathway involved in terpenoid biosynthetic process / 1-deoxy-D-xylulose-5-phosphate reductoisomerase / 1-deoxy-D-xylulose-5-phosphate reductoisomerase activity / NADPH binding / manganese ion binding
Similarity search - Function
1-deoxy-D-xylulose 5-phosphate reductoisomerase / 1-deoxy-D-xylulose 5-phosphate reductoisomerase, N-terminal / 1-deoxy-D-xylulose 5-phosphate reductoisomerase, C-terminal / DXP reductoisomerase C-terminal domain / DXP reductoisomerase, C-terminal domain superfamily / 1-deoxy-D-xylulose 5-phosphate reductoisomerase / 1-deoxy-D-xylulose 5-phosphate reductoisomerase C-terminal domain / DXP reductoisomerase C-terminal domain / RNA polymerase sigma factor, region 2, helix turn helix motif / Rna Polymerase Sigma Factor; Chain: A ...1-deoxy-D-xylulose 5-phosphate reductoisomerase / 1-deoxy-D-xylulose 5-phosphate reductoisomerase, N-terminal / 1-deoxy-D-xylulose 5-phosphate reductoisomerase, C-terminal / DXP reductoisomerase C-terminal domain / DXP reductoisomerase, C-terminal domain superfamily / 1-deoxy-D-xylulose 5-phosphate reductoisomerase / 1-deoxy-D-xylulose 5-phosphate reductoisomerase C-terminal domain / DXP reductoisomerase C-terminal domain / RNA polymerase sigma factor, region 2, helix turn helix motif / Rna Polymerase Sigma Factor; Chain: A / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-1UQ / MANGANESE (III) ION / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplastic
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsKunfermann, A. / Bacher, A. / Groll, M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters.
Authors: Kunfermann, A. / Lienau, C. / Illarionov, B. / Held, J. / Grawert, T. / Behrendt, C.T. / Werner, P. / Hahn, S. / Eisenreich, W. / Riederer, U. / Mordmuller, B. / Bacher, A. / Fischer, M. / Groll, M. / Kurz, T.
History
DepositionMay 13, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2013Group: Database references
Revision 1.2Feb 12, 2014Group: Database references
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast
B: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,7407
Polymers97,3042
Non-polymers1,4365
Water4,252236
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5110 Å2
ΔGint-26 kcal/mol
Surface area31540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.460, 78.120, 99.990
Angle α, β, γ (deg.)90.00, 91.53, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.735367, 0.627642, 0.255542), (0.629531, -0.772285, 0.085239), (0.25085, 0.09819, -0.963033)-7.24105, 0.64235, 48.08458

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Components

#1: Protein 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast / 1-deoxyxylulose-5-phosphate reductoisomerase / DOXP reductoisomerase / DXP reductoisomerase


Mass: 48652.004 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: codon optimized form, DXR, synthetic / Plasmid: pQEIspCplasart / Production host: Escherichia coli (E. coli) / Strain (production host): M15 pREP4
References: UniProt: O96693, 1-deoxy-D-xylulose-5-phosphate reductoisomerase
#2: Chemical ChemComp-MN3 / MANGANESE (III) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Chemical ChemComp-1UQ / [(S)-({2-[hydroxy(methyl)amino]-2-oxoethyl}sulfanyl)(phenyl)methyl]phosphonic acid


Mass: 291.261 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H14NO5PS
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 236 / 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: 2.06 Å3/Da / Density % sol: 40.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 2% PEG4000, 100 mM NaAc, 15% MPD, pH 5.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: May 13, 2011
RadiationMonochromator: LN2 cooled fixed-exit. Si(111) monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→40 Å / Num. all: 53593 / Num. obs: 52039 / % possible obs: 97.1 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.8 % / Rmerge(I) obs: 0.082 / Net I/σ(I): 12.7
Reflection shellResolution: 2→2.1 Å / Rmerge(I) obs: 0.533 / Mean I/σ(I) obs: 3 / % possible all: 96.7

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Processing

Software
NameVersionClassification
XDSdata scaling
PHASERphasing
REFMAC5.6.0117refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3AU8; IspC Plasmodium Apo

3au8


Resolution: 2→15 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.922 / SU B: 12.089 / SU ML: 0.151 / Cross valid method: THROUGHOUT / ESU R Free: 0.189 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.24871 2601 5 %RANDOM
Rwork0.18485 ---
all0.195 49419 --
obs0.18806 49419 97.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.982 Å2
Baniso -1Baniso -2Baniso -3
1--2.41 Å20 Å2-0.09 Å2
2--4.26 Å20 Å2
3----1.85 Å2
Refinement stepCycle: LAST / Resolution: 2→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6468 0 86 236 6790
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.026686
X-RAY DIFFRACTIONr_angle_refined_deg1.21.9319025
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8165808
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.41726.392291
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.925151257
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.827156
X-RAY DIFFRACTIONr_chiral_restr0.080.21048
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214798
X-RAY DIFFRACTIONr_rigid_bond_restr4.55136686
X-RAY DIFFRACTIONr_sphericity_free31.56588
X-RAY DIFFRACTIONr_sphericity_bonded19.79356702
LS refinement shellResolution: 2→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 185 -
Rwork0.207 3485 -
obs--96.35 %
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)
10.1209-0.00140.00070.04490.04010.08170.0150.0507-0.01810.02470.0007-0.01380.02360.0098-0.01570.07290.0014-0.01210.0508-0.00750.07219.11-11.19814.192
20.4144-0.221-0.16070.13020.13180.24130.0223-0.01460.1052-0.0090.0102-0.0532-0.01340.0035-0.03250.0706-0.0040.00060.0059-0.00340.09023.32122.12638.241
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A77 - 485
2X-RAY DIFFRACTION1A502 - 503
3X-RAY DIFFRACTION2B77 - 484
4X-RAY DIFFRACTION2B502

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