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- PDB-6n82: Crystal structure of human FPPS in complex with an allosteric inh... -

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Basic information

Entry
Database: PDB / ID: 6n82
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor YF-02037
ComponentsFarnesyl pyrophosphate synthaseDimethylallyltranstransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / Transferase-Transferase Inhibitor complex
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
TRIETHYLENE GLYCOL / PHOSPHATE ION / Chem-YF7 / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsPark, J. / Schilling, M.A. / Berghuis, A.M.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Chirality-Driven Mode of Binding of alpha-Aminophosphonic Acid-Based Allosteric Inhibitors of the Human Farnesyl Pyrophosphate Synthase (hFPPS).
Authors: Feng, Y. / Park, J. / Li, S.G. / Boutin, R. / Viereck, P. / Schilling, M.A. / Berghuis, A.M. / Tsantrizos, Y.S.
History
DepositionNov 28, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 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)44,5719
Polymers43,1451
Non-polymers1,4268
Water2,072115
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,14218
Polymers86,2902
Non-polymers2,85216
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area6900 Å2
ΔGint-64 kcal/mol
Surface area27790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.920, 110.920, 77.530
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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Protein , 1 types, 1 molecules F

#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: 43144.980 Da / Num. of mol.: 1 / Fragment: 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

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Non-polymers , 7 types, 123 molecules

#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-YF7 / [(1S)-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: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


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


Mass: 18.015 Da / Num. of mol.: 115 / 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: 2.76 Å3/Da / Density % sol: 55.49 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 1.36M tri-sodium citrate 15% (v/v) glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2→78.43 Å / Num. obs: 33080 / % possible obs: 99.8 % / Redundancy: 12.9 % / Biso Wilson estimate: 46.204 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.043 / Rpim(I) all: 0.013 / Rrim(I) all: 0.045 / Net I/σ(I): 25.9
Reflection shellResolution: 2→2.04 Å / Redundancy: 12.4 % / Rmerge(I) obs: 1.244 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 1624 / CC1/2: 0.874 / Rpim(I) all: 0.365 / Rrim(I) all: 1.298 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4XQR

4xqr


Resolution: 2→78.43 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.961 / SU B: 10.752 / SU ML: 0.13 / Cross valid method: THROUGHOUT / ESU R: 0.136 / ESU R Free: 0.127 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20442 1704 5.2 %RANDOM
Rwork0.17218 ---
obs0.17377 31318 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 70.04 Å2
Baniso -1Baniso -2Baniso -3
1--3.87 Å20 Å20 Å2
2---3.87 Å20 Å2
3---7.73 Å2
Refinement stepCycle: 1 / Resolution: 2→78.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2698 0 89 115 2902
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0142870
X-RAY DIFFRACTIONr_bond_other_d0.0040.0172535
X-RAY DIFFRACTIONr_angle_refined_deg1.8671.693901
X-RAY DIFFRACTIONr_angle_other_deg1.1361.6635897
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1375343
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.30623.176148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.25415457
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.8331514
X-RAY DIFFRACTIONr_chiral_restr0.0880.2363
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023214
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02560
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_it2.6894.3121372
X-RAY DIFFRACTIONr_mcbond_other2.6784.311371
X-RAY DIFFRACTIONr_mcangle_it3.8186.4491715
X-RAY DIFFRACTIONr_mcangle_other3.8196.4511716
X-RAY DIFFRACTIONr_scbond_it3.9454.91497
X-RAY DIFFRACTIONr_scbond_other3.7894.8881493
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.2267.2082181
X-RAY DIFFRACTIONr_long_range_B_refined9.12953.2353437
X-RAY DIFFRACTIONr_long_range_B_other8.97452.9593417
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.002→2.054 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.377 138 -
Rwork0.361 2265 -
obs--98.93 %
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)
15.2709-0.826-1.6223.17330.00482.3698-0.07320.5122-0.312-0.43470.150.54390.2056-0.5614-0.07680.0784-0.0716-0.07860.14740.03450.10848.388684.82415.0765
25.08560.1694-0.02773.6141-2.10763.39780.0959-0.5865-0.58220.2465-0.2012-0.08360.26410.40390.10530.1102-0.00970.00990.27270.05470.08312.182479.676235.9305
32.70040.59192.1274.6117-2.11387.72780.0495-0.402-0.61210.446-0.1506-1.00871.01911.5250.10110.48870.3716-0.09361.11350.49970.800126.101264.017145.7133
46.6279-4.25773.04956.0825-3.82493.81510.1945-0.3672-0.60250.2755-0.1450.40460.41720.1009-0.04950.2759-0.03920.09040.27830.09580.26851.6474.977941.123
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F8 - 167
2X-RAY DIFFRACTION2F168 - 276
3X-RAY DIFFRACTION3F277 - 300
4X-RAY DIFFRACTION4F301 - 350

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