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- PDB-5djr: Crystal structure of human FPPS in complex with biaryl compound 6 -

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Basic information

Entry
Database: PDB / ID: 5djr
TitleCrystal structure of human FPPS in complex with biaryl compound 6
ComponentsFarnesyl pyrophosphate synthase
KeywordsTRANSFERASE / ISOPRENE BIOSYNTHESIS / CHOLESTEROL BIOSYNTHESIS
Function / homology
Function and homology information


geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / (2E,6E)-farnesyl diphosphate synthase / farnesyl diphosphate biosynthetic process / dimethylallyltranstransferase activity / Cholesterol biosynthesis / geranyltranstransferase activity / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / RNA binding ...geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / (2E,6E)-farnesyl diphosphate synthase / farnesyl diphosphate biosynthetic process / dimethylallyltranstransferase activity / Cholesterol biosynthesis / geranyltranstransferase activity / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / RNA binding / nucleoplasm / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Farnesyl pyrophosphate synthase-like / Polyprenyl synthases signature 2. / Polyprenyl synthases signature 1. / Polyprenyl synthetase, conserved site / Polyprenyl synthetase / Polyprenyl synthetase / Farnesyl Diphosphate Synthase / Farnesyl Diphosphate Synthase / Isoprenoid synthase domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
1H,1'H-4,4'-biindole-2-carboxylic acid / PHOSPHATE ION / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsRondeau, J.M. / Bourgier, E. / Lehmann, S.
Citation
Journal: Chemmedchem / Year: 2015
Title: Discovery of Novel Allosteric Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding.
Authors: Marzinzik, A.L. / Amstutz, R. / Bold, G. / Bourgier, E. / Cotesta, S. / Glickman, J.F. / Gotte, M. / Henry, C. / Lehmann, S. / Hartwieg, J.C. / Ofner, S. / Pelle, X. / Roddy, T.P. / Rondeau, ...Authors: Marzinzik, A.L. / Amstutz, R. / Bold, G. / Bourgier, E. / Cotesta, S. / Glickman, J.F. / Gotte, M. / Henry, C. / Lehmann, S. / Hartwieg, J.C. / Ofner, S. / Pelle, X. / Roddy, T.P. / Rondeau, J.M. / Stauffer, F. / Stout, S.J. / Widmer, A. / Zimmermann, J. / Zoller, T. / Jahnke, W.
#1: Journal: Nat.Chem.Biol. / Year: 2010
Title: Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery.
Authors: Jahnke, W. / Rondeau, J.M. / Cotesta, S. / Marzinzik, A. / Pelle, X. / Geiser, M. / Strauss, A. / Gotte, M. / Bitsch, F. / Hemmig, R. / Henry, C. / Lehmann, S. / Glickman, J.F. / Roddy, T.P. ...Authors: Jahnke, W. / Rondeau, J.M. / Cotesta, S. / Marzinzik, A. / Pelle, X. / Geiser, M. / Strauss, A. / Gotte, M. / Bitsch, F. / Hemmig, R. / Henry, C. / Lehmann, S. / Glickman, J.F. / Roddy, T.P. / Stout, S.J. / Green, J.R.
#2: Journal: to be published
Title: Tuning bone affinity into non-bisphosphonate FPPS inhibitors: a general strategy for targeting drugs acting on bone
Authors: Jahnke, W. / Bold, G. / Marzinzik, A. / Ofner, S. / Pelle, X. / Cotesta, S. / Bourgier, E. / Lehmann, S. / Henry, C. / Hemmig, R. / Stauffer, F. / Mueller-Hartwieg, C. / Green, J.R. / Rondeau, J.M.
History
DepositionSep 2, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2015Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7395
Polymers40,1841
Non-polymers5554
Water1,38777
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,47910
Polymers80,3682
Non-polymers1,1118
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area5700 Å2
ΔGint-44 kcal/mol
Surface area29280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.320, 111.320, 77.310
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Farnesyl pyrophosphate synthase / FPS / (2E / 6E)-farnesyl diphosphate synthase / Dimethylallyltranstransferase / Farnesyl ...FPS / (2E / 6E)-farnesyl diphosphate synthase / Dimethylallyltranstransferase / Farnesyl diphosphate synthase / Geranyltranstransferase


Mass: 40183.855 Da / Num. of mol.: 1 / Fragment: Residues 6-253
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FDPS, FPS, KIAA1293 / Plasmid: pET28 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): tuner
References: UniProt: P14324, (2E,6E)-farnesyl diphosphate synthase, dimethylallyltranstransferase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-5BK / 1H,1'H-4,4'-biindole-2-carboxylic acid


Mass: 276.289 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12N2O2
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.98 Å3/Da / Density % sol: 58.73 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5.3 / Details: 1.2M sodium potassium phosphate, 25% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Oct 4, 2005 / Details: MIRRORS
RadiationMonochromator: MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.4→78.8 Å / Num. obs: 19004 / % possible obs: 96.6 % / Observed criterion σ(I): -3 / Redundancy: 13.5 % / Biso Wilson estimate: 58.8 Å2 / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.105 / Rrim(I) all: 0.109 / Net I/σ(I): 18.34 / Num. measured all: 256333
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Highest resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.4-2.466.90.7791.2841.679012143212971.38790.6
2.46-2.530.9391.0733.0718003138713441.11696.9
2.53-2.60.9520.8823.7418575135513140.91597
2.6-2.680.9680.6694.7818077131212780.69497.4
2.68-2.770.9760.5485.4717843129412530.56896.8
2.77-2.860.9810.4596.2517231122812130.47698.8
2.86-2.970.9890.3547.7216597118111590.36798.1
2.97-3.090.9890.3018.9816493116911570.31299
3.09-3.230.9940.21212.6515363111110730.21996.6
3.23-3.390.9960.15616.8314748105310310.16297.9
3.39-3.570.9980.11522.681400910249870.1296.4
3.57-3.790.9980.08529.15131019479270.08897.9
3.79-4.050.9990.07134.13120209118510.07493.4
4.05-4.370.9990.05939.56113358568140.06195.1
4.37-4.790.9990.0544.5104587847490.05295.5
4.79-5.360.9990.04846.195197196860.0595.4
5.36-6.190.9990.05542.386116466320.05797.8
6.19-7.580.9990.04447.8172565535450.04698.6
7.58-10.720.9990.03357.7154174414320.03598
10.720.9990.03650.5426652722620.03896.3

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Processing

Software
NameVersionClassification
XDSSeptember 26, 2012data reduction
XSCALENovember 3, 2014data scaling
CNX2005phasing
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→24.09 Å / Cor.coef. Fo:Fc: 0.9458 / Cor.coef. Fo:Fc free: 0.9329 / SU R Cruickshank DPI: 0.313 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.321 / SU Rfree Blow DPI: 0.223 / SU Rfree Cruickshank DPI: 0.224
RfactorNum. reflection% reflectionSelection details
Rfree0.2346 940 5 %RANDOM
Rwork0.2031 ---
obs0.2047 18797 96.3 %-
Displacement parametersBiso max: 187.72 Å2 / Biso mean: 73.65 Å2 / Biso min: 32.48 Å2
Baniso -1Baniso -2Baniso -3
1-7.0284 Å20 Å20 Å2
2--7.0284 Å20 Å2
3----14.0569 Å2
Refine analyzeLuzzati coordinate error obs: 0.408 Å
Refinement stepCycle: final / Resolution: 2.4→24.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2766 0 59 77 2902
Biso mean--88.29 58.23 -
Num. residues----342
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1002SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes81HARMONIC2
X-RAY DIFFRACTIONt_gen_planes406HARMONIC5
X-RAY DIFFRACTIONt_it2887HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion356SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3416SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2887HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3912HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.66
X-RAY DIFFRACTIONt_other_torsion17.26
LS refinement shellResolution: 2.4→2.54 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.308 134 4.99 %
Rwork0.2518 2554 -
all0.2545 2688 -
obs--96.3 %
Refinement TLS params.Method: refined / Details: FPPS / Origin x: 10.1926 Å / Origin y: 80.3246 Å / Origin z: 27.7392 Å
111213212223313233
T-0.318 Å2-0.0185 Å20.0146 Å2--0.2938 Å20.0265 Å2--0.071 Å2
L3.2286 °20.7282 °2-1.8736 °2-1.917 °2-0.7844 °2--2.381 °2
S-0.1376 Å °-0.244 Å °-0.3453 Å °0.004 Å °0.0429 Å °0.2073 Å °0.2344 Å °-0.027 Å °0.0947 Å °
Refinement TLS groupSelection: All / Selection details: { F|* }

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