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- PDB-5djv: Crystal structure of human FPPS in complex with biaryl compound 8e -

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Basic information

Entry
Database: PDB / ID: 5djv
TitleCrystal structure of human FPPS in complex with biaryl compound 8e
ComponentsFarnesyl pyrophosphate synthaseDimethylallyltranstransferase
KeywordsTRANSFERASE / ISOPRENE BIOSYNTHESIS / CHOLESTEROL BIOSYNTHESIS
Function / homology
Function and homology information


geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / farnesyl diphosphate biosynthetic process / (2E,6E)-farnesyl diphosphate synthase / geranyltranstransferase activity / dimethylallyltranstransferase activity / Cholesterol biosynthesis / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / RNA binding ...geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / farnesyl diphosphate biosynthetic process / (2E,6E)-farnesyl diphosphate synthase / geranyltranstransferase activity / dimethylallyltranstransferase activity / Cholesterol biosynthesis / 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 1. / Polyprenyl synthases signature 2. / 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
Chem-5BL / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 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 1.0Oct 7, 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)40,5482
Polymers40,1841
Non-polymers3641
Water48627
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,0974
Polymers80,3682
Non-polymers7292
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area4020 Å2
ΔGint-24 kcal/mol
Surface area29830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.880, 111.880, 74.020
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 / Dimethylallyltranstransferase / 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: UNP residues 72-419
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-5BL / 8-(naphthalen-1-yl)-6-(1H-pyrrol-2-yl)quinoline-2-carboxylic acid


Mass: 364.396 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H16N2O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 27 / 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: 2.89 Å3/Da / Density % sol: 57.4 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 4.7 / Details: 1.2M sodium potassium phosphate, 25% glycerol

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Data collection

DiffractionMean temperature: 88 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 14, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionHighest resolution: 2.3 Å / Num. obs: 21202 / % possible obs: 98.8 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 54.91 Å2 / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.069 / Rrim(I) all: 0.074 / Net I/σ(I): 17.8 / Num. measured all: 151724
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Highest resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.3-2.367.160.8351.4211.810276157715721.5499.7
2.36-2.420.8961.1962.2410232139413931.28599.9
2.42-2.490.9210.972.7710881149414881.04399.6
2.49-2.570.9570.7473.5210887148614820.80399.7
2.57-2.660.970.5234.7710866148914860.56299.8
2.66-2.750.9840.4085.99481129812960.43999.8
2.75-2.850.9880.3297.029265126612640.35499.8
2.85-2.970.9920.2488.99350128412790.26799.6
2.97-3.10.9950.18911.258702119911940.20399.6
3.1-3.250.9970.12615.688343115411470.13699.4
3.25-3.430.9980.08920.098040112811120.09698.6
3.43-3.640.9980.06526.067533106310470.0798.5
3.64-3.890.9990.04833.7168589809550.05297.4
3.89-4.20.9990.03938.9562509198730.04295
4.2-4.60.9990.03445.4759248558340.03797.5
4.6-5.140.9990.03149.1453547827560.03496.7
5.14-5.940.9990.03646.6447777016830.03997.4
5.94-7.270.9990.02949.1940896015970.03299.3
7.27-10.290.9990.02659.5831074874780.02898.2
10.290.9990.02656.7215092922660.02891.1

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.11.5refinement
XDSSeptember 26, 2012data reduction
XSCALENovember 3, 2014data scaling
CNX2005phasing
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.3→24.52 Å / Cor.coef. Fo:Fc: 0.9527 / Cor.coef. Fo:Fc free: 0.9254 / SU R Cruickshank DPI: 0.257 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.256 / SU Rfree Blow DPI: 0.201 / SU Rfree Cruickshank DPI: 0.204
RfactorNum. reflection% reflectionSelection details
Rfree0.2423 1059 5 %RANDOM
Rwork0.2088 ---
obs0.2105 21187 98.91 %-
Displacement parametersBiso max: 204.75 Å2 / Biso mean: 94.73 Å2 / Biso min: 42.61 Å2
Baniso -1Baniso -2Baniso -3
1-7.1756 Å20 Å20 Å2
2--7.1756 Å20 Å2
3----14.3512 Å2
Refine analyzeLuzzati coordinate error obs: 0.468 Å
Refinement stepCycle: final / Resolution: 2.3→24.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2774 0 28 27 2829
Biso mean--87.5 57.3 -
Num. residues----343
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1000SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes82HARMONIC2
X-RAY DIFFRACTIONt_gen_planes405HARMONIC5
X-RAY DIFFRACTIONt_it2865HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion357SEMIHARMONIC5
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_contact3363SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2865HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3883HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.57
X-RAY DIFFRACTIONt_other_torsion18.58
LS refinement shellResolution: 2.3→2.41 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2428 139 4.97 %
Rwork0.2337 2656 -
all0.2342 2795 -
obs--98.91 %
Refinement TLS params.Method: refined / Origin x: 10.1394 Å / Origin y: 80.5855 Å / Origin z: 26.33 Å
111213212223313233
T-0.362 Å2-0.0222 Å20.0161 Å2--0.3761 Å20.0642 Å2--0.4614 Å2
L4.1868 °20.8928 °2-1.5909 °2-2.6753 °2-0.5456 °2--1.9355 °2
S-0.123 Å °-0.293 Å °-0.714 Å °0.0895 Å °0.0465 Å °0.2739 Å °0.2857 Å °-0.0334 Å °0.0765 Å °
Refinement TLS groupSelection details: { F|* }

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