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

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Basic information

Entry
Database: PDB / ID: 5ksx
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor AM-02-072
ComponentsFarnesyl pyrophosphate synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / 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-7AM / PHOSPHATE ION / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.65 Å
AuthorsPark, J. / Matralis, A. / 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
DepositionJul 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, 2017Group: Author supporting evidence / Category: pdbx_audit_support
Revision 1.3Oct 4, 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)44,1774
Polymers43,1451
Non-polymers1,0323
Water1,36976
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,3548
Polymers86,2902
Non-polymers2,0646
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area4300 Å2
ΔGint-42 kcal/mol
Surface area28300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.480, 110.480, 75.200
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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-7AM / [[(2~{S})-2-[[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoyl]amino]phosphonic acid


Mass: 468.465 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21N4O4PS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 2.66 Å3/Da / Density % sol: 53.75 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.6 M sodium phosphate, 0.6 M potassium phosphate, 25% glycerol, 0.075 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: May 28, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.65→55.24 Å / Num. obs: 14007 / % possible obs: 99.8 % / Redundancy: 12.5 % / Biso Wilson estimate: 41.62 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.085 / Net I/σ(I): 26.7
Reflection shellResolution: 2.65→2.72 Å / Redundancy: 7.7 % / Rmerge(I) obs: 1.037 / Mean I/σ(I) obs: 1.9 / CC1/2: 0.748 / % possible all: 98

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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: 4XQR

4xqr


Resolution: 2.65→55.24 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.925 / SU B: 25.637 / SU ML: 0.253 / Cross valid method: THROUGHOUT / ESU R: 0.555 / ESU R Free: 0.303 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24291 702 5 %RANDOM
Rwork0.17096 ---
obs0.17451 13266 99.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 62.585 Å2
Baniso -1Baniso -2Baniso -3
1--3.5 Å20 Å20 Å2
2---3.5 Å20 Å2
3---6.99 Å2
Refinement stepCycle: 1 / Resolution: 2.65→55.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2683 0 69 76 2828
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.022814
X-RAY DIFFRACTIONr_bond_other_d0.0030.022616
X-RAY DIFFRACTIONr_angle_refined_deg2.0751.9933825
X-RAY DIFFRACTIONr_angle_other_deg1.1743.0055985
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3645336
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.26324.615130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.35115453
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5671513
X-RAY DIFFRACTIONr_chiral_restr0.1050.2419
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023185
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02662
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_it1.7343.5081359
X-RAY DIFFRACTIONr_mcbond_other1.6773.5011358
X-RAY DIFFRACTIONr_mcangle_it2.7065.2291690
X-RAY DIFFRACTIONr_mcangle_other2.7055.2381691
X-RAY DIFFRACTIONr_scbond_it2.6434.0491454
X-RAY DIFFRACTIONr_scbond_other2.6424.0551455
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.9786.0052135
X-RAY DIFFRACTIONr_long_range_B_refined6.50831.4693477
X-RAY DIFFRACTIONr_long_range_B_other6.50731.4963478
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.652→2.721 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 37 -
Rwork0.302 947 -
obs--98.01 %
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)
112.39293.1388-5.65184.2368-1.89636.26760.09430.84710.1366-0.41530.13930.6954-0.0767-0.9059-0.23350.2321-0.0272-0.10510.2471-0.07150.21477.849682.67436.7732
25.1853-0.1116-1.36062.3197-0.33442.1802-0.07240.1129-0.277-0.20570.08120.40150.1247-0.365-0.00890.0226-0.0224-0.03230.06430.01180.08259.720485.05218.641
36.2455-2.09230.90824.9213-3.03673.93510.0248-0.4967-0.45180.2369-0.1665-0.10060.1630.5670.14170.07810.0150.01490.2540.05450.139311.426978.682436.0584
46.6693-4.51181.90015.2846-2.45942.17130.1062-0.3466-0.68580.2533-0.1720.10630.30860.40980.06570.27650.04830.04970.35890.14330.39298.479171.651640.981
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F9 - 50
2X-RAY DIFFRACTION2F51 - 178
3X-RAY DIFFRACTION3F179 - 279
4X-RAY DIFFRACTION4F280 - 351

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