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- PDB-6n83: Crystal structure of human FPPS in complex with an allosteric inh... -

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Basic information

Entry
Database: PDB / ID: 6n83
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor YF-02037
ComponentsFarnesyl pyrophosphate synthase
KeywordsTRANSFERASE / 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
PHOSPHATE ION / Chem-YL6 / 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)43,7895
Polymers43,1451
Non-polymers6444
Water1,856103
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,57710
Polymers86,2902
Non-polymers1,2888
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area4930 Å2
ΔGint-74 kcal/mol
Surface area28620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.080, 111.080, 76.730
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-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.: 1 / Source method: obtained synthetically / Formula: C21H18ClFN3O3PS
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / 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: 55.16 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.08 M TrisHCl ph 8.5, 1.6 M Ammonium phosphate, 20% (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→111.08 Å / Num. obs: 32849 / % possible obs: 99.3 % / Redundancy: 13 % / Biso Wilson estimate: 48.823 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.043 / Rpim(I) all: 0.013 / Rrim(I) all: 0.045 / Net I/σ(I): 25.7
Reflection shellResolution: 2→2.03 Å / Redundancy: 13.1 % / Rmerge(I) obs: 1.375 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1609 / CC1/2: 0.861 / Rpim(I) all: 0.392 / Rrim(I) all: 1.431 / % 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→78.67 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.962 / SU B: 14.772 / SU ML: 0.172 / Cross valid method: THROUGHOUT / ESU R: 0.145 / ESU R Free: 0.135 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21745 1696 5.2 %RANDOM
Rwork0.18633 ---
obs0.18802 31095 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 75.052 Å2
Baniso -1Baniso -2Baniso -3
1--4.86 Å20 Å20 Å2
2---4.86 Å20 Å2
3---9.71 Å2
Refinement stepCycle: 1 / Resolution: 2→78.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2694 0 38 103 2835
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0142821
X-RAY DIFFRACTIONr_bond_other_d0.0030.0172518
X-RAY DIFFRACTIONr_angle_refined_deg1.6691.6693836
X-RAY DIFFRACTIONr_angle_other_deg1.0521.6425863
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6935344
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.64923.217143
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.60415462
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.7591513
X-RAY DIFFRACTIONr_chiral_restr0.0840.2360
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023172
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02549
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_it2.5994.4861376
X-RAY DIFFRACTIONr_mcbond_other2.5974.4841375
X-RAY DIFFRACTIONr_mcangle_it3.876.7111720
X-RAY DIFFRACTIONr_mcangle_other3.8696.7141721
X-RAY DIFFRACTIONr_scbond_it3.5624.8411444
X-RAY DIFFRACTIONr_scbond_other3.4154.8271441
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.9997.1332111
X-RAY DIFFRACTIONr_long_range_B_refined8.80153.8463360
X-RAY DIFFRACTIONr_long_range_B_other8.65653.4833336
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.436 108 -
Rwork0.377 2267 -
obs--98.71 %
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)
16.595-0.9168-4.50541.98730.98235.2752-0.15431.0979-0.3977-0.57650.21090.70940.297-1.0377-0.05660.2635-0.2228-0.23220.37830.07310.41695.563182.148111.551
24.75340.0009-1.31292.7483-0.41922.2805-0.06630.1553-0.1692-0.14670.09310.4470.1218-0.2962-0.02680.0499-0.0478-0.01380.06330.00390.080411.679286.472918.8184
36.5352-1.41551.37524.7554-3.19144.85530.1299-0.3931-0.59640.138-0.1980.05030.37840.46580.0680.1161-0.01230.04570.2720.00860.11411.053179.531835.4472
46.398-2.73971.80313.7763-2.35713.06040.1126-0.5251-0.67290.2969-0.212-0.00040.48280.43330.09940.34430.05640.07750.41290.15990.4349.528371.995542.169
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F9 - 71
2X-RAY DIFFRACTION2F72 - 178
3X-RAY DIFFRACTION3F179 - 273
4X-RAY DIFFRACTION4F274 - 350

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