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- PDB-4ng6: The effects of Lysine 200 and Phenylalanine 239 Farnesyl Pyrophos... -

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Basic information

Entry
Database: PDB / ID: 4ng6
TitleThe effects of Lysine 200 and Phenylalanine 239 Farnesyl Pyrophosphate Synthase (FPPS) mutations on the catalytic activity, crystal structure and inhibition by nitrogen containing bisphosphonates
ComponentsFarnesyl pyrophosphate synthase
KeywordsTRANSFERASE / Alpha-Helical Prenyltransferase / Isoprene Biosynthesis / Lipid Synthesis / Steroid Biosynthesis / Isoprenoid Pathway / Cholesterol Synthesis / Bisphosphonates
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
3-METHYLBUT-3-ENYL TRIHYDROGEN DIPHOSPHATE / Chem-RIS / Farnesyl pyrophosphate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsTsoumpra, M.K. / Muniz, J.R.C. / Barnett, B.L. / Pilka, E. / Kwaasi, A.A. / Kavanagh, K.L. / Evdokimov, A. / Walter, R.L. / Ebetino, F.H. / Oppermann, U. ...Tsoumpra, M.K. / Muniz, J.R.C. / Barnett, B.L. / Pilka, E. / Kwaasi, A.A. / Kavanagh, K.L. / Evdokimov, A. / Walter, R.L. / Ebetino, F.H. / Oppermann, U. / Russell, R.G.G. / Dunford, J.E.
CitationJournal: TO BE PUBLISHED
Title: The effects of Lysine 200 and Phenylalanine 239 Farnesyl Pyrophosphate Synthase (FPPS) mutations on the catalytic activity, crystal structure and inhibition by nitrogen containing bisphosphonates
Authors: Tsoumpra, M.K. / Muniz, J.R.C. / Barnett, B.L. / Pilka, E. / Kwaasi, A.A. / Kavanagh, K.L. / Evdokimov, A. / Walter, R.L. / Ebetino, F.H. / Oppermann, U. / Russell, R.G.G. / Dunford, J.E.
History
DepositionNov 1, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 19, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Database references / Structure summary / Category: pdbx_database_related
Item: _chem_comp.pdbx_synonyms / _pdbx_database_related.db_id
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,7316
Polymers43,1291
Non-polymers6025
Water3,819212
1
A: Farnesyl pyrophosphate synthase
hetero molecules

A: Farnesyl pyrophosphate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,46212
Polymers86,2582
Non-polymers1,20410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_555-y,-x,-z+1/21
Buried area6970 Å2
ΔGint-79 kcal/mol
Surface area27610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.740, 111.740, 66.600
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-556-

HOH

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Components

#1: Protein Farnesyl pyrophosphate synthase / FPP synthase / FPS / (2E / 6E)-farnesyl diphosphate synthase / Dimethylallyltranstransferase / ...FPP synthase / FPS / (2E / 6E)-farnesyl diphosphate synthase / Dimethylallyltranstransferase / Farnesyl diphosphate synthase / Geranyltranstransferase


Mass: 43128.961 Da / Num. of mol.: 1 / Fragment: UNP residues 67-419 / Mutation: K200L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FDPS, FPS, KIAA1293 / Plasmid: Pet 11 derivative / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: P14324, (2E,6E)-farnesyl diphosphate synthase, dimethylallyltranstransferase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-IPE / 3-METHYLBUT-3-ENYL TRIHYDROGEN DIPHOSPHATE / ISOPENTENYL PYROPHOSPHATE


Mass: 246.092 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H12O7P2
#4: Chemical ChemComp-RIS / 1-HYDROXY-2-(3-PYRIDINYL)ETHYLIDENE BIS-PHOSPHONIC ACID / Risedronate


Mass: 283.112 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H11NO7P2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 212 / 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: 2.41 Å3/Da / Density % sol: 48.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.2 M NH4CL, PEG 6000, 10% Ethylene Glycol, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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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 RAXIS IV++ / Detector: IMAGE PLATE / Details: 2011-02-03
RadiationMonochromator: Graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.35→33.98 Å / Num. all: 17999 / Num. obs: 17960 / % possible obs: 99.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 8.6 % / Biso Wilson estimate: 46.36 Å2 / Rmerge(I) obs: 0.161 / Rsym value: 0.161 / Net I/σ(I): 10.3
Reflection shellResolution: 2.35→2.49 Å / % possible all: 95.7

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
BUSTER2.10.0refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3CP6

3cp6


Resolution: 2.35→33.98 Å / Cor.coef. Fo:Fc: 0.9463 / Cor.coef. Fo:Fc free: 0.9111 / SU R Cruickshank DPI: 0.303 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.23 914 5.09 %RANDOM
Rwork0.1777 ---
obs0.1803 17960 99.2 %-
all-17999 --
Displacement parametersBiso mean: 46.45 Å2
Baniso -1Baniso -2Baniso -3
1-3.925 Å20 Å20 Å2
2--3.925 Å20 Å2
3----7.85 Å2
Refine analyzeLuzzati coordinate error obs: 0.285 Å
Refinement stepCycle: LAST / Resolution: 2.35→33.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2735 0 34 212 2981
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012895HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.983941HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1380SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes79HARMONIC2
X-RAY DIFFRACTIONt_gen_planes419HARMONIC5
X-RAY DIFFRACTIONt_it2895HARMONIC20
X-RAY DIFFRACTIONt_nbd4SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.54
X-RAY DIFFRACTIONt_other_torsion2.94
X-RAY DIFFRACTIONt_chiral_improper_torsion366SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3680SEMIHARMONIC4
LS refinement shellResolution: 2.35→2.49 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2559 145 5.16 %
Rwork0.218 2663 -
all0.22 2808 -
obs--99.2 %
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)
13.8608-0.3238-2.85383.1879-2.39310.1206-0.04-0.0894-0.04190.1140.0909-0.04030.1856-0.3002-0.0508-0.096-0.10360.0295-0.08840.101-0.0016-29.9387-0.190626.7052
20.5631.0080.85310.4108-0.60671.29440.0082-0.2231-0.0940.2686-0.069200.05210.15880.0609-0.0512-0.00210.0483-0.0392-0.02730.2538-24.405915.820433.5271
30.8316-0.56220.28293.29560.04661.1720.0445-0.0213-0.13620.1455-0.06450.35470.1889-0.07040.02-0.0987-0.0477-0.0007-0.1290.00220.1592-28.53945.503418.6291
42.3631-0.45-0.14580.26560.29330.4346-0.0184-0.1861-0.05150.38950.00150.07780.1616-0.0080.0168-0.0327-0.0173-0.0228-0.09070.00220.0829-17.925410.349123.154
50.00520.56080.36750.03650.82680-0.01980.08610.0729-0.13940.01590.0093-0.00610.03550.0038-0.0544-0.0225-0.01-0.1299-0.0190.1437-18.978313.13438.3697
62.08010.3630.79242.1773-0.07540-0.0220.21090.1331-0.52120.1182-0.0251-0.04950.1018-0.0962-0.01630.0011-0.0123-0.1677-0.05490.1557-29.701417.5351-1.846
70.5551-0.47640.57672.3605-0.54051.3221-0.00360.09850.0646-0.35160.0247-0.01580.24910.0984-0.0211-0.0345-0.016-0.0745-0.2033-0.06490.1152-26.27592.30973.854
81.407-0.86480.85632.5477-0.73880.07570.13780.1670.0012-0.54420.02510.54420.0182-0.2215-0.1629-0.03180.0084-0.1358-0.1636-0.01840.1958-43.042921.3347-2.1507
90.0110.1954-0.51770.52580.55011.1351-0.06070.16180.1063-0.37170.08780.25310.147-0.2146-0.0271-0.0653-0.026-0.152-0.1861-0.01410.2243-41.9448.0732-4.5873
101.09442.38411.20532.21111.69990.4238-0.01880.0507-0.0469-0.12680.06060.18140.2591-0.0627-0.0418-0.0225-0.0214-0.0721-0.14410.02230.158-32.5302-5.19355.5256
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|10 - 28}A10 - 28
2X-RAY DIFFRACTION2{A|29 - 52}A29 - 52
3X-RAY DIFFRACTION3{A|53 - 124}A53 - 124
4X-RAY DIFFRACTION4{A|125 - 152}A125 - 152
5X-RAY DIFFRACTION5{A|153 - 177}A153 - 177
6X-RAY DIFFRACTION6{A|178 - 206}A178 - 206
7X-RAY DIFFRACTION7{A|207 - 249}A207 - 249
8X-RAY DIFFRACTION8{A|250 - 294}A250 - 294
9X-RAY DIFFRACTION9{A|295 - 332}A295 - 332
10X-RAY DIFFRACTION10{A|333 - 353}A333 - 353

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