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- PDB-5juz: Crystal structure of human FPPS in complex with an allosteric inh... -

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Basic information

Entry
Database: PDB / ID: 5juz
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor CL-06-057
ComponentsFarnesyl pyrophosphate synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / (2E,6E)-farnesyl diphosphate synthase / Cholesterol biosynthesis / farnesyl diphosphate biosynthetic process / dimethylallyltranstransferase activity / (2E,6E)-farnesyl diphosphate synthase activity / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / peroxisome ...geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / (2E,6E)-farnesyl diphosphate synthase / Cholesterol biosynthesis / farnesyl diphosphate biosynthetic process / dimethylallyltranstransferase activity / (2E,6E)-farnesyl diphosphate synthase activity / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / peroxisome / mitochondrial matrix / 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-YL4 / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsPark, J. / Magder, A. / Leung, C.Y. / Tsantrizos, Y.S. / Berghuis, A.M.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase.
Authors: Park, J. / Leung, C.Y. / Matralis, A.N. / Lacbay, C.M. / Tsakos, M. / Fernandez De Troconiz, G. / Berghuis, A.M. / Tsantrizos, Y.S.
History
DepositionMay 10, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Sep 27, 2023Group: 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
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)43,6694
Polymers43,1451
Non-polymers5243
Water1,71195
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,3398
Polymers86,2902
Non-polymers1,0496
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area4280 Å2
ΔGint-64 kcal/mol
Surface area27880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.900, 110.900, 77.000
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 43144.980 Da / Num. of mol.: 1 / Fragment: UNP residues 67-419
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FDPS, FPS, KIAA1293 / Production host: Escherichia coli (E. coli)
References: UniProt: P14324, (2E,6E)-farnesyl diphosphate synthase, dimethylallyltranstransferase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-YL4 / [(R)-(2,3-dihydro-1-benzofuran-5-yl){[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}methyl]phosphonic acid


Mass: 453.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20N3O4PS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / 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: 2.74 Å3/Da / Density % sol: 55.17 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.6 M sodium phosphate, 0.6 M potassium phosphate, 25% glycerol, 0.075 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Apr 21, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.4→78.42 Å / Num. obs: 19304 / % possible obs: 99.8 % / Redundancy: 9.3 % / Biso Wilson estimate: 46.933 Å2 / Rmerge(I) obs: 0.098 / Net I/σ(I): 14.1
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 9.4 % / Rmerge(I) obs: 0.931 / Mean I/σ(I) obs: 2.3 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0123phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4QXS

4qxs


Resolution: 2.4→78.42 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.942 / SU B: 19.608 / SU ML: 0.213 / Cross valid method: THROUGHOUT / ESU R: 0.269 / ESU R Free: 0.215 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22718 951 4.9 %RANDOM
Rwork0.1805 ---
obs0.18285 18322 99.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 64.524 Å2
Baniso -1Baniso -2Baniso -3
1--2.84 Å20 Å20 Å2
2---2.84 Å20 Å2
3---5.69 Å2
Refinement stepCycle: 1 / Resolution: 2.4→78.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2610 0 33 95 2738
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.022701
X-RAY DIFFRACTIONr_bond_other_d0.0030.022500
X-RAY DIFFRACTIONr_angle_refined_deg2.1351.9823679
X-RAY DIFFRACTIONr_angle_other_deg1.1683.0035709
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4725333
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.48524.37119
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.55615421
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.4271512
X-RAY DIFFRACTIONr_chiral_restr0.1130.2413
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023076
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02627
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_it1.8753.3811341
X-RAY DIFFRACTIONr_mcbond_other1.873.381340
X-RAY DIFFRACTIONr_mcangle_it2.9865.061671
X-RAY DIFFRACTIONr_mcangle_other2.9855.0611672
X-RAY DIFFRACTIONr_scbond_it2.5153.6661359
X-RAY DIFFRACTIONr_scbond_other2.5153.6691360
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.9235.4322008
X-RAY DIFFRACTIONr_long_range_B_refined6.67528.823256
X-RAY DIFFRACTIONr_long_range_B_other6.67428.8343257
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.401→2.463 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.258 64 -
Rwork0.302 1333 -
obs--99.5 %
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)
19.422.2272-1.59835.791.38147.3457-0.10981.1292-0.3153-0.58020.26170.78540.7137-1.5476-0.15190.2723-0.2327-0.20760.5273-0.04270.50762.017581.33739.965
24.6359-0.2592-1.9292.6937-0.01562.698-0.06850.2243-0.244-0.32370.08490.37390.2076-0.3733-0.01640.0572-0.0407-0.03390.05580.00390.191110.897785.092817.5253
35.9363-1.46910.34375.1916-3.05344.4246-0.0158-0.5294-0.48060.2431-0.1773-0.09850.29280.52490.19310.10550.01910.06140.24640.05260.290710.804479.244636.3063
46.2212-3.51751.30285.423-2.32533.32740.086-0.2627-0.44170.233-0.3168-0.37010.55290.59330.23080.28750.03650.07440.31720.1250.48478.154972.158441.9704
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F10 - 30
2X-RAY DIFFRACTION2F35 - 179
3X-RAY DIFFRACTION3F180 - 277
4X-RAY DIFFRACTION4F278 - 350

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