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

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Basic information

Entry
Database: PDB / ID: 5djp
TitleCrystal structure of human FPPS in complex with biaryl compound 5
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
4-(naphthalen-1-yl)-1H-indole-2-carboxylic acid / PHOSPHATE ION / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / 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. / Goette, 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. / Goette, 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)40,5663
Polymers40,1841
Non-polymers3822
Water99155
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,1326
Polymers80,3682
Non-polymers7654
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area4490 Å2
ΔGint-38 kcal/mol
Surface area29330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.430, 111.430, 71.764
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 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-5BJ / 4-(naphthalen-1-yl)-1H-indole-2-carboxylic acid


Mass: 287.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H13NO2
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


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


Mass: 18.015 Da / Num. of mol.: 55 / 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: 2.77 Å3/Da / Density % sol: 55.63 %
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: Jan 17, 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→50 Å / Num. obs: 18108 / % possible obs: 99.5 % / Redundancy: 12 % / Biso Wilson estimate: 54.36 Å2 / Rmerge(I) obs: 0.072 / Χ2: 1.088 / Net I/av σ(I): 30.696 / Net I/σ(I): 13.4 / Num. measured all: 217855
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.4-2.4911.20.48817650.97599.9
2.49-2.59110.37517831.00699.8
2.59-2.710.80.27117770.96499.8
2.7-2.8510.80.2217890.96499.8
2.85-3.0211.30.17117920.91699.9
3.02-3.2612.30.12217970.998100
3.26-3.5813.30.08718261.07199.9
3.582-4.113.60.06218121.16899.6
4.103-5.1713.40.04818391.43299.2
5.173-5012.60.03919281.24696.9

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
CNX2002phasing
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→25.29 Å / Cor.coef. Fo:Fc: 0.9392 / Cor.coef. Fo:Fc free: 0.9251 / SU R Cruickshank DPI: 0.364 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.372 / SU Rfree Blow DPI: 0.239 / SU Rfree Cruickshank DPI: 0.24
RfactorNum. reflection% reflectionSelection details
Rfree0.2452 848 4.85 %RANDOM
Rwork0.2189 ---
obs0.2202 17499 96.2 %-
Displacement parametersBiso max: 163.51 Å2 / Biso mean: 68.85 Å2 / Biso min: 31.83 Å2
Baniso -1Baniso -2Baniso -3
1-6.0673 Å20 Å20 Å2
2--6.0673 Å20 Å2
3----12.1346 Å2
Refine analyzeLuzzati coordinate error obs: 0.415 Å
Refinement stepCycle: final / Resolution: 2.4→25.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2774 0 27 55 2856
Biso mean--88.37 53.18 -
Num. residues----343
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d999SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes82HARMONIC2
X-RAY DIFFRACTIONt_gen_planes404HARMONIC5
X-RAY DIFFRACTIONt_it2862HARMONIC20
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_contact3439SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2862HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3879HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion2.67
X-RAY DIFFRACTIONt_other_torsion17.4
LS refinement shellResolution: 2.4→2.54 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2974 128 4.58 %
Rwork0.2639 2667 -
all0.2655 2795 -
obs--96.2 %
Refinement TLS params.Method: refined / Details: FPPS / Origin x: 9.7006 Å / Origin y: 80.4828 Å / Origin z: 25.4966 Å
111213212223313233
T-0.2704 Å2-0.0244 Å2-0.0163 Å2--0.2985 Å20.0435 Å2--0.1269 Å2
L2.7593 °20.7194 °2-0.7701 °2-1.4001 °2-0.4868 °2--1.8422 °2
S-0.0017 Å °-0.0833 Å °-0.4355 Å °0.0053 Å °0.0675 Å °0.1195 Å °0.2561 Å °-0.1028 Å °-0.0658 Å °
Refinement TLS groupSelection: All / Selection details: { F|* }

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