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- PDB-8wtq: HUMAN SQUALENE SYNTHASE IN COMPLEX WITH {1-[2-Chloro-5-(2,2-dimet... -

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Basic information

Entry
Database: PDB / ID: 8wtq
TitleHUMAN SQUALENE SYNTHASE IN COMPLEX WITH {1-[2-Chloro-5-(2,2-dimethyl-propyl)-13-(2-methoxy-phenyl)-6-oxo-6,7,10,11-tetrahydro-5H,9H,13H-12-oxa-5,8-diaza-benzocycloundecene-8-carbonyl]-piperidin-4-yl}-acetic acid
ComponentsSqualene synthase
KeywordsTRANSFERASE / TERPENOID SYNTHASE FOLD / ISOPRENE BIOSYNTHESIS / LIPID SYNTHESIS / MULTIFUNCTIONAL ENZYME / OXIDOREDUCTASE / STEROID BIOSYNTHESIS / STEROL BIOSYNTHESIS / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


squalene synthase / farnesyl diphosphate metabolic process / squalene synthase [NAD(P)H] activity / Cholesterol biosynthesis / steroid biosynthetic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / PPARA activates gene expression / endoplasmic reticulum membrane / endoplasmic reticulum ...squalene synthase / farnesyl diphosphate metabolic process / squalene synthase [NAD(P)H] activity / Cholesterol biosynthesis / steroid biosynthetic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / PPARA activates gene expression / endoplasmic reticulum membrane / endoplasmic reticulum / metal ion binding / membrane
Similarity search - Function
Squalene synthase-like / Trans-isoprenyl diphosphate synthases, eukaryotic-type / Squalene and phytoene synthases signature 2. / Squalene/phytoene synthase, conserved site / Squalene and phytoene synthases signature 1. / Trans-isoprenyl diphosphate synthases, head-to-head / Squalene/phytoene synthase / Squalene/phytoene synthase / Isoprenoid synthase domain superfamily
Similarity search - Domain/homology
: / PHOSPHATE ION / Squalene synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsSuzuki, M. / Haginoya, N. / Suzuki, M. / Ishigai, Y. / Terayama, K. / Kanda, A. / Sugita, K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Novel 11-Membered Templates as Squalene Synthase Inhibitors.
Authors: Haginoya, N. / Suzuki, M. / Suzuki, M. / Ishigai, Y. / Terayama, K. / Kanda, A. / Sugita, K.
History
DepositionOct 19, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 22, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Squalene synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8623
Polymers39,1671
Non-polymers6952
Water5,837324
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area150 Å2
ΔGint-4 kcal/mol
Surface area14140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.382, 60.017, 86.049
Angle α, β, γ (deg.)90.00, 117.07, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-803-

HOH

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Components

#1: Protein Squalene synthase / SQS / SS / FPP:FPP farnesyltransferase / Farnesyl-diphosphate farnesyltransferase / Farnesyl- ...SQS / SS / FPP:FPP farnesyltransferase / Farnesyl-diphosphate farnesyltransferase / Farnesyl-diphosphate farnesyltransferase 1


Mass: 39166.699 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FDFT1 / Plasmid: PA-426 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): PLYSS / References: UniProt: P37268, squalene synthase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-KUO / 2-[1-[[(10~{S})-13-chloranyl-2-(2,2-dimethylpropyl)-10-(2-methoxyphenyl)-3-oxidanylidene-9-oxa-2,5-diazabicyclo[9.4.0]pentadeca-1(15),11,13-trien-5-yl]carbonyl]piperidin-4-yl]ethanoic acid


Mass: 600.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H42ClN3O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 324 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.56 Å3/Da / Density % sol: 52.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20% PEG8000/ 50mM KH2PO4/ 1mM DTT. Complex crystal was prepared by soaking in 20% PEG8000/ 50mM KH2PO4, pH 6/ 1mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Feb 1, 2003
RadiationMonochromator: confocal mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→27.98 Å / Num. obs: 26702 / % possible obs: 99.1 % / Redundancy: 2.45 % / Rmerge(I) obs: 0.088 / Rrim(I) all: 0.088 / Χ2: 1.24 / Net I/σ(I): 6.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsΧ2% possible all
2-2.072.40.2332.826521.0399.6
2.07-2.152.420.1883.526701.0499.6
2.15-2.252.410.1713.926751.08100
2.25-2.372.440.1724.126871.42100
2.37-2.522.440.1484.827021.36100
2.52-2.712.450.1295.326511.2999.9
2.71-2.992.470.1096.426961.4699.6
2.99-3.422.490.0858.126651.5598.9
3.42-4.32.490.0512.426741.2198.1
4.3-27.982.520.03814.526300.9494.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
d*TREK7.1SSIdata scaling
d*TREK7.1SSIdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→25 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.929 / SU B: 3.322 / SU ML: 0.093 / Cross valid method: THROUGHOUT / ESU R: 0.154 / ESU R Free: 0.146 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.20582 1348 5.1 %RANDOM
Rwork0.15668 ---
obs0.1591 25334 98.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.819 Å2
Baniso -1Baniso -2Baniso -3
1-0.54 Å20 Å2-0.4 Å2
2--0.33 Å20 Å2
3----0.31 Å2
Refinement stepCycle: 1 / Resolution: 2→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2660 0 47 324 3031
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0122770
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6411.6563757
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2875334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.36322.759145
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.67615463
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5471516
X-RAY DIFFRACTIONr_chiral_restr0.1040.2365
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022091
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.4461.441339
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.1872.4681673
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.4411.6531431
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.420.5413590
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.07 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.23 133 -
Rwork0.185 2455 -
obs--99.58 %

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