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- PDB-5jv0: Crystal structure of human FPPS in complex with an allosteric inh... -

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Basic information

Entry
Database: PDB / ID: 5jv0
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor CL-08-038
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 / cytoplasm / cytosol
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-YL5 / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsPark, J. / 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)44,6676
Polymers43,1451
Non-polymers1,5225
Water2,000111
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,33512
Polymers86,2902
Non-polymers3,04510
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area5120 Å2
ΔGint-105 kcal/mol
Surface area28990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.540, 111.540, 75.980
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-YL5 / [(1R)-2-(3-fluorophenyl)-1-{[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}ethyl]phosphonic acid


Mass: 443.431 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H19FN3O3PS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 55.09 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.85 M lithium sulfate, 0.425 M ammonium sulfate, 15% glycerol, 0.085 M tri-sodium citrate, pH 5.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.4→41.7 Å / Num. obs: 17150 / % possible obs: 88.4 % / Redundancy: 12.1 % / Biso Wilson estimate: 36.381 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 31.9
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.713 / Mean I/σ(I) obs: 2.1 / % possible all: 52.4

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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→41.7 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.93 / SU B: 19.642 / SU ML: 0.215 / Cross valid method: THROUGHOUT / ESU R: 0.361 / ESU R Free: 0.254 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23504 863 5 %RANDOM
Rwork0.17636 ---
obs0.17936 16251 88.24 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 56.403 Å2
Baniso -1Baniso -2Baniso -3
1--3.41 Å20 Å20 Å2
2---3.41 Å20 Å2
3---6.82 Å2
Refinement stepCycle: 1 / Resolution: 2.4→41.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2701 0 100 111 2912
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.022891
X-RAY DIFFRACTIONr_bond_other_d0.0030.022651
X-RAY DIFFRACTIONr_angle_refined_deg2.1322.0063939
X-RAY DIFFRACTIONr_angle_other_deg1.1913.0066070
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6715343
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.16824.593135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.39715460
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.9241514
X-RAY DIFFRACTIONr_chiral_restr0.1160.2426
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023282
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02683
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_it1.5332.8771372
X-RAY DIFFRACTIONr_mcbond_other1.5242.8751371
X-RAY DIFFRACTIONr_mcangle_it2.494.3071715
X-RAY DIFFRACTIONr_mcangle_other2.4924.3091716
X-RAY DIFFRACTIONr_scbond_it2.4373.441518
X-RAY DIFFRACTIONr_scbond_other2.4373.4461519
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.6655.1062224
X-RAY DIFFRACTIONr_long_range_B_refined7.67227.1233554
X-RAY DIFFRACTIONr_long_range_B_other7.67227.1463555
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.396→2.458 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 38 -
Rwork0.301 687 -
obs--51.24 %
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)
19.5421.1912-5.84846.1084-1.820312.3263-0.31520.9620.0297-0.63180.47270.42920.5817-1.0024-0.15750.2264-0.0849-0.18060.3217-0.05320.23621.999382.26319.5443
27.18790.3638-4.14791.67430.01094.70930.05120.69-0.2007-0.3550.05350.3761-0.0061-0.7207-0.10470.1346-0.0577-0.08470.15550.01610.12945.624484.232412.988
37.2104-2.086-0.61152.8608-0.78241.9939-0.08480.2255-0.3553-0.25620.06630.20060.3014-0.31720.01850.0868-0.0619-0.00340.0605-0.01070.022413.352583.249715.4707
410.5912-5.18764.78846.7453-4.66865.5969-0.0026-0.41610.14730.02840.06860.046-0.1154-0.0888-0.06590.0537-0.0270.03840.0543-0.02560.032112.688892.733925.5501
55.3684-1.091.15174.6714-2.75474.08590.075-0.4985-0.63960.2643-0.2955-0.30450.30610.62420.22050.14940.01870.02180.35360.13660.172513.426677.511637.5867
65.4723-3.82172.55275.1621-3.83093.59470.143-0.3445-0.770.0554-0.1040.37880.38950.1975-0.0390.29440.01610.08590.26430.09450.26683.584273.970140.2753
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F8 - 34
2X-RAY DIFFRACTION2F35 - 76
3X-RAY DIFFRACTION3F77 - 147
4X-RAY DIFFRACTION4F148 - 179
5X-RAY DIFFRACTION5F182 - 293
6X-RAY DIFFRACTION6F294 - 350

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