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- PDB-6n7z: Crystal structure of human FPPS in complex with an allosteric inh... -

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Basic information

Entry
Database: PDB / ID: 6n7z
TitleCrystal structure of human FPPS in complex with an allosteric inhibitor YF-02037
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 / geranyltranstransferase activity / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / RNA binding ...geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / (2E,6E)-farnesyl diphosphate synthase / Cholesterol biosynthesis / farnesyl diphosphate biosynthetic process / dimethylallyltranstransferase activity / geranyltranstransferase activity / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / 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-KF7 / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.55 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)43,6984
Polymers43,1451
Non-polymers5533
Water1,33374
1
F: Farnesyl pyrophosphate synthase
hetero molecules

F: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,3968
Polymers86,2902
Non-polymers1,1066
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area4830 Å2
ΔGint-45 kcal/mol
Surface area27800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.862, 110.862, 75.038
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-KF7 / [(1S)-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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / 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: 2.67 Å3/Da / Density % sol: 53.97 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging 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: LIQUID ANODE / Type: BRUKER METALJET / Wavelength: 1.3418 Å
DetectorType: BRUKER PHOTON 100 / Detector: CCD / Date: Dec 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.3418 Å / Relative weight: 1
ReflectionResolution: 2.55→54.21 Å / Num. obs: 15822 / % possible obs: 99.9 % / Redundancy: 15.98 % / Rmerge(I) obs: 0.096 / Net I/σ(I): 14.46
Reflection shellResolution: 2.55→2.65 Å / Redundancy: 16.27 % / Rmerge(I) obs: 0.571 / Mean I/σ(I) obs: 2.73 / Num. unique obs: 1687 / % possible all: 100

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Processing

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

4xqr


Resolution: 2.55→44.63 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.927 / SU B: 37.731 / SU ML: 0.366 / Cross valid method: THROUGHOUT / ESU R: 0.519 / ESU R Free: 0.317 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28103 726 4.7 %RANDOM
Rwork0.23211 ---
obs0.23439 14745 97.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 71.301 Å2
Baniso -1Baniso -2Baniso -3
1--7.03 Å20 Å20 Å2
2---7.03 Å20 Å2
3---14.07 Å2
Refinement stepCycle: 1 / Resolution: 2.55→44.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2619 0 36 74 2729
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0142737
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172431
X-RAY DIFFRACTIONr_angle_refined_deg1.5841.6673722
X-RAY DIFFRACTIONr_angle_other_deg1.0171.6475643
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.895337
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.27122.701137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.33315432
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3951514
X-RAY DIFFRACTIONr_chiral_restr0.0770.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023091
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02542
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_it1.5913.431351
X-RAY DIFFRACTIONr_mcbond_other1.5913.4291350
X-RAY DIFFRACTIONr_mcangle_it2.6375.1361687
X-RAY DIFFRACTIONr_mcangle_other2.6365.1371688
X-RAY DIFFRACTIONr_scbond_it1.7123.6551386
X-RAY DIFFRACTIONr_scbond_other1.7113.6621387
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.8165.4512036
X-RAY DIFFRACTIONr_long_range_B_refined7.37942.1223322
X-RAY DIFFRACTIONr_long_range_B_other7.37241.9843314
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.55→2.616 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 54 -
Rwork0.319 1106 -
obs--99.83 %
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)
15.458-0.2129-1.26052.9605-0.21222.4461-0.01110.3275-0.2951-0.41160.03810.50870.2237-0.3909-0.0270.3168-0.0784-0.05570.28650.00220.10249.675484.899815.7175
25.1029-0.70781.06653.1686-1.63553.15890.0958-0.4998-0.90520.3458-0.1376-0.02540.39920.31480.04180.4656-0.00920.05620.56810.12980.18939.632676.328337.9185
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1F11 - 178
2X-RAY DIFFRACTION2F179 - 350

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