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- PDB-6n7y: Crystal structure of human FPPS in complex with an allosteric inh... -

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Basic information

Entry
Database: PDB / ID: 6n7y
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor MIT-01-102
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 / 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
Chem-KFA / PHOSPHATE ION / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsPark, J. / 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)43,7574
Polymers43,1451
Non-polymers6133
Water2,396133
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,5158
Polymers86,2902
Non-polymers1,2256
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area5250 Å2
ΔGint-45 kcal/mol
Surface area28670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.240, 111.240, 77.300
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: 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-KFA / [(1R)-1-{[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}-2-phenylethyl]phosphonic acid


Mass: 425.441 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20N3O3PS
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


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


Mass: 18.015 Da / Num. of mol.: 133 / 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: 55.62 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1.6 M Ammonium phosphate, 20% glycerol, 0.08 M TrisHCl

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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 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2→78.66 Å / Num. obs: 33209 / % possible obs: 99.8 % / Redundancy: 13 % / Biso Wilson estimate: 49.102 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.014 / Rrim(I) all: 0.049 / Net I/σ(I): 23.2
Reflection shellResolution: 2→2.04 Å / Redundancy: 11.9 % / Rmerge(I) obs: 1.385 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 1628 / CC1/2: 0.826 / Rpim(I) all: 0.415 / Rrim(I) all: 1.447 / % possible all: 99.3

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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→78.66 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.965 / SU B: 10.698 / SU ML: 0.131 / Cross valid method: THROUGHOUT / ESU R: 0.135 / ESU R Free: 0.125 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20244 1647 5 %RANDOM
Rwork0.17393 ---
obs0.17544 31506 99.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 73.191 Å2
Baniso -1Baniso -2Baniso -3
1--3.78 Å20 Å20 Å2
2---3.78 Å20 Å2
3---7.56 Å2
Refinement stepCycle: 1 / Resolution: 2→78.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2657 0 40 133 2830
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0142826
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172512
X-RAY DIFFRACTIONr_angle_refined_deg1.7331.6683847
X-RAY DIFFRACTIONr_angle_other_deg1.091.6445848
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5865344
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.76923.061147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.18815457
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.431514
X-RAY DIFFRACTIONr_chiral_restr0.0940.2360
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.023189
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02556
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_it2.7744.521370
X-RAY DIFFRACTIONr_mcbond_other2.7564.5191369
X-RAY DIFFRACTIONr_mcangle_it3.9626.7621716
X-RAY DIFFRACTIONr_mcangle_other3.9616.7641717
X-RAY DIFFRACTIONr_scbond_it3.9654.9981455
X-RAY DIFFRACTIONr_scbond_other3.9654.9861452
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.7537.3382126
X-RAY DIFFRACTIONr_long_range_B_refined8.24854.2213356
X-RAY DIFFRACTIONr_long_range_B_other8.14253.7113322
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.001→2.053 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 121 -
Rwork0.328 2269 -
obs--99.13 %
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)
14.2305-0.1372-1.70282.9468-0.0672.5799-0.05030.1091-0.2617-0.15040.09330.32620.2234-0.3548-0.0430.0327-0.0414-0.02330.05840.02230.064610.602584.55320.0895
25.7564-2.63580.62525.9607-2.01893.06430.0371-0.3912-0.70120.3663-0.2212-0.23190.41740.48020.18420.2372-0.00130.05810.36120.10440.28759.341673.657939.7264
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F10 - 217
2X-RAY DIFFRACTION2F218 - 350

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