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- PDB-5jv1: Crystal structure of human FPPS in complex with an allosteric inh... -

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Basic information

Entry
Database: PDB / ID: 5jv1
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor CL-08-066
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-YL6 / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 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 1.2May 10, 2017Group: Refinement description
Revision 1.3Sep 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)44,2935
Polymers43,1451
Non-polymers1,1484
Water1,27971
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,58610
Polymers86,2902
Non-polymers2,2968
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area5140 Å2
ΔGint-106 kcal/mol
Surface area27800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.050, 111.050, 76.200
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-YL6 / [(1R)-1-{[6-(3-chloro-4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}-2-(3-fluorophenyl)ethyl]phosphonic acid


Mass: 477.876 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18ClFN3O3PS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 2.72 Å3/Da / Density % sol: 54.82 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 25.5% PEG 8000, 0.17 M sodium acetate, 15% glycerol, 0.085 M sodium cacodylate, pH 6.5

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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: 2.3→49.66 Å / Num. obs: 21646 / % possible obs: 99.5 % / Redundancy: 9.6 % / Biso Wilson estimate: 47.783 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 21.3
Reflection shellResolution: 2.3→2.36 Å / Redundancy: 9.6 % / Rmerge(I) obs: 0.982 / Mean I/σ(I) obs: 3.1 / % possible all: 98.4

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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: 2.3→49.66 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.948 / SU B: 16.528 / SU ML: 0.187 / Cross valid method: THROUGHOUT / ESU R: 0.231 / ESU R Free: 0.2 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23153 1123 5.2 %RANDOM
Rwork0.18106 ---
obs0.18376 20478 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 68.78 Å2
Baniso -1Baniso -2Baniso -3
1--3.38 Å20 Å20 Å2
2---3.38 Å20 Å2
3---6.77 Å2
Refinement stepCycle: 1 / Resolution: 2.3→49.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2635 0 72 71 2778
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.022768
X-RAY DIFFRACTIONr_bond_other_d0.0020.022547
X-RAY DIFFRACTIONr_angle_refined_deg2.1361.9963773
X-RAY DIFFRACTIONr_angle_other_deg1.163.0045816
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.765333
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.89824.355124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.32115431
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4411513
X-RAY DIFFRACTIONr_chiral_restr0.1250.2419
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.023132
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02647
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_it2.3193.8381341
X-RAY DIFFRACTIONr_mcbond_other2.2973.8351340
X-RAY DIFFRACTIONr_mcangle_it3.4855.7461671
X-RAY DIFFRACTIONr_mcangle_other3.4855.7481672
X-RAY DIFFRACTIONr_scbond_it3.3744.3591427
X-RAY DIFFRACTIONr_scbond_other3.3734.3641428
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.8736.4632103
X-RAY DIFFRACTIONr_long_range_B_refined7.7534.4563349
X-RAY DIFFRACTIONr_long_range_B_other7.74934.4773350
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 74 -
Rwork0.289 1476 -
obs--98.48 %
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)
19.21655.8624-6.864210.7189-4.08766.7059-0.1550.5520.1125-0.37040.30070.69270.3593-1.0873-0.14570.1973-0.1054-0.15310.4065-0.03570.3921.707481.066410.2504
26.07120.3923-4.58152.60970.235.49060.06280.6915-0.1617-0.39910.02180.4954-0.0264-0.7342-0.08460.0899-0.031-0.09910.14680.00640.27886.070483.570613.0851
36.5985-2.1544-1.05783.6147-0.46412.0539-0.08660.3202-0.2901-0.28010.00730.26030.2601-0.33270.07940.0497-0.0397-0.01310.0583-0.02890.148213.185982.919115.5974
410.412-5.19674.79036.2292-4.02686.10540.0784-0.27110.11780.0378-0.02080.133-0.15270.0267-0.05750.0196-0.01190.04650.017-0.02150.178412.54492.358925.5938
55.3044-1.68961.28785.66-3.76265.37350.0604-0.5396-0.57190.3298-0.2714-0.23310.31340.68580.2110.13060.03110.01190.33340.09340.365613.154977.596337.6681
66.0885-4.17633.22185.9233-3.71053.75070.2232-0.3614-0.6250.1364-0.09430.2870.43290.1868-0.12890.20490.03250.07270.24050.11150.48133.640973.819740.6707
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F9 - 30
2X-RAY DIFFRACTION2F35 - 76
3X-RAY DIFFRACTION3F77 - 147
4X-RAY DIFFRACTION4F148 - 179
5X-RAY DIFFRACTION5F182 - 293
6X-RAY DIFFRACTION6F294 - 350

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