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- PDB-6c57: Crystal structure of mutant human geranylgeranyl pyrophosphate sy... -

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Basic information

Entry
Database: PDB / ID: 6c57
TitleCrystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in complex with bisphosphonate inhibitor FV0109
ComponentsGeranylgeranyl pyrophosphate synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / ISOPRENOID PATHWAY / ISOPENTENYL TRANSFERASE / TRANSFERASE INHIBITOR / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


isoprenoid metabolic process / geranylgeranyl diphosphate biosynthetic process / geranylgeranyl diphosphate synthase / farnesyltranstransferase activity / Transferases; Transferring alkyl or aryl groups, other than methyl groups / geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / farnesyl diphosphate biosynthetic process / (2E,6E)-farnesyl diphosphate synthase / geranyltranstransferase activity ...isoprenoid metabolic process / geranylgeranyl diphosphate biosynthetic process / geranylgeranyl diphosphate synthase / farnesyltranstransferase activity / Transferases; Transferring alkyl or aryl groups, other than methyl groups / geranyl diphosphate biosynthetic process / dimethylallyltranstransferase / farnesyl diphosphate biosynthetic process / (2E,6E)-farnesyl diphosphate synthase / geranyltranstransferase activity / prenyltransferase activity / dimethylallyltranstransferase activity / Cholesterol biosynthesis / isoprenoid biosynthetic process / Activation of gene expression by SREBF (SREBP) / Z disc / perinuclear region of cytoplasm / nucleoplasm / identical protein binding / metal ion binding / cytosol / cytoplasm
Similarity search - Function
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-FV9 / Geranylgeranyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsPark, J. / Bin, X. / Vincent, F. / Tsantrizos, Y.S. / Berghuis, A.M.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors.
Authors: Lacbay, C.M. / Waller, D.D. / Park, J. / Gomez Palou, M. / Vincent, F. / Huang, X.F. / Ta, V. / Berghuis, A.M. / Sebag, M. / Tsantrizos, Y.S.
History
DepositionJan 15, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 5, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Geranylgeranyl pyrophosphate synthase
B: Geranylgeranyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,3913
Polymers74,8532
Non-polymers5381
Water905
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3360 Å2
ΔGint-34 kcal/mol
Surface area23280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)185.450, 185.450, 114.200
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: PHE / Beg label comp-ID: PHE / End auth comp-ID: MET / End label comp-ID: MET / Refine code: 0 / Auth seq-ID: -2 - 294 / Label seq-ID: 20 - 316

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Geranylgeranyl pyrophosphate synthase / GGPPSase / (2E / 6E)-farnesyl diphosphate synthase / Dimethylallyltranstransferase / Farnesyl ...GGPPSase / (2E / 6E)-farnesyl diphosphate synthase / Dimethylallyltranstransferase / Farnesyl diphosphate synthase / Farnesyltranstransferase / Geranylgeranyl diphosphate synthase / Geranyltranstransferase


Mass: 37426.488 Da / Num. of mol.: 2 / Mutation: Y246D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GGPS1 / Production host: Escherichia coli (E. coli)
References: UniProt: O95749, Transferases; Transferring alkyl or aryl groups, other than methyl groups, dimethylallyltranstransferase, geranylgeranyl diphosphate synthase, (2E,6E)-farnesyl diphosphate synthase
#2: Chemical ChemComp-FV9 / {[(2-{3-[(4-fluorobenzene-1-carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-4-yl)amino]methylene}bis(phosphonic acid)


Mass: 538.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17FN4O7P2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 3.28 Å3/Da / Density % sol: 62.49 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 1.7 M ammonium sulfate, 4.25% isopropanol, 15% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1.38052 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.38052 Å / Relative weight: 1
ReflectionResolution: 3.5→97.24 Å / Num. obs: 12861 / % possible obs: 100 % / Redundancy: 12.9 % / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.015 / Net I/σ(I): 26.9
Reflection shellResolution: 3.5→3.59 Å / Redundancy: 12.5 % / Rmerge(I) obs: 1.271 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 940 / Rpim(I) all: 0.385 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2Q80

2q80


Resolution: 3.5→97.24 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.927 / SU B: 54.841 / SU ML: 0.381 / Cross valid method: THROUGHOUT / ESU R Free: 0.524 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25221 669 5.2 %RANDOM
Rwork0.19802 ---
obs0.20085 12192 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 160.71 Å2
Baniso -1Baniso -2Baniso -3
1--2.1 Å20 Å20 Å2
2---2.1 Å20 Å2
3---4.2 Å2
Refinement stepCycle: 1 / Resolution: 3.5→97.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4108 0 35 5 4148
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0194236
X-RAY DIFFRACTIONr_bond_other_d0.0020.023755
X-RAY DIFFRACTIONr_angle_refined_deg2.0011.9755774
X-RAY DIFFRACTIONr_angle_other_deg1.1523.0018665
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6325524
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.44624.947190
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.63115656
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7351513
X-RAY DIFFRACTIONr_chiral_restr0.1040.2661
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0214733
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02851
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_it6.74311.4432117
X-RAY DIFFRACTIONr_mcbond_other6.74311.4442116
X-RAY DIFFRACTIONr_mcangle_it9.90717.1712634
X-RAY DIFFRACTIONr_mcangle_other9.90517.172635
X-RAY DIFFRACTIONr_scbond_it7.48611.8942119
X-RAY DIFFRACTIONr_scbond_other7.48411.8982120
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other11.18517.6843141
X-RAY DIFFRACTIONr_long_range_B_refined13.9654984
X-RAY DIFFRACTIONr_long_range_B_other13.9644985
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 15920 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 3.5→3.591 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.341 56 -
Rwork0.269 884 -
obs--99.89 %
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)
11.8166-0.5127-1.50661.96810.04886.1878-0.1397-0.5241-1.09630.3844-0.47150.18910.36650.58740.61120.55940.1484-0.00310.50750.30760.7143-37.740310.6242-39.103
28.48871.8633-3.54173.3431-1.93212.3961-0.1218-1.1015-0.31790.637-0.3681-0.35470.04450.54550.48990.520.19070.00160.34690.01390.1907-29.925526.1891-38.0353
36.59590.9285-2.49642.9828-0.36792.9223-0.1031-0.4491-0.83180.2597-0.3325-0.63930.0180.66610.43550.5080.1961-0.11080.5630.21810.3385-17.568119.7919-36.0277
43.2097-1.2048-2.553210.56151.41894.9290.0161-0.0228-0.08660.4033-0.1686-0.05280.0409-0.05350.15250.55720.1315-0.18080.69540.15990.467-18.628615.4263-20.3967
56.25971.3335-4.94493.2858-1.31984.7026-0.02850.40750.08050.3313-0.3010.5518-0.305-0.69350.32950.24010.1523-0.09740.3102-0.28860.3464-47.588330.5956-47.2598
62.4576-0.6253-0.86195.495410.331920.8838-0.37190.0961-0.4381-0.2178-0.26020.47180.0301-0.09730.63220.40780.06890.07960.2668-0.08570.3172-50.041512.3508-52.4256
71.58330.29472.15223.18873.70067.0280.31340.5288-0.1031-0.6784-0.40170.4268-0.0965-0.29360.08830.67510.0169-0.05590.8457-0.22090.6601-61.644220.1429-54.514
82.91621.44341.85793.90670.62621.3286-0.07830.4584-0.064-0.51240.32360.82730.062-0.0642-0.24520.79690.0409-0.24481.5741-0.20241.0185-70.888923.0793-60.5279
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-3 - 106
2X-RAY DIFFRACTION2A107 - 156
3X-RAY DIFFRACTION3A157 - 265
4X-RAY DIFFRACTION4A266 - 295
5X-RAY DIFFRACTION5B-2 - 116
6X-RAY DIFFRACTION6B117 - 138
7X-RAY DIFFRACTION7B139 - 221
8X-RAY DIFFRACTION8B222 - 294

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