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- PDB-7ezf: Indole-2-carboxylic acid derivatives as allosteric inhibitors of ... -

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Basic information

Entry
Database: PDB / ID: 7ezf
TitleIndole-2-carboxylic acid derivatives as allosteric inhibitors of fructose-1,6-bisphosphatase
ComponentsFructose-1,6-bisphosphatase 1
KeywordsHYDROLASE / fructose-1 / 6-bisphosphatase / indole dicarboxylic acid derivative inhibitor
Function / homology
Function and homology information


cellular response to raffinose / cellular hypotonic salinity response / fructose-bisphosphatase / cellular response to phorbol 13-acetate 12-myristate / fructose 1,6-bisphosphate 1-phosphatase activity / negative regulation of Ras protein signal transduction / fructose 1,6-bisphosphate metabolic process / cellular response to magnesium ion / Gluconeogenesis / fructose metabolic process ...cellular response to raffinose / cellular hypotonic salinity response / fructose-bisphosphatase / cellular response to phorbol 13-acetate 12-myristate / fructose 1,6-bisphosphate 1-phosphatase activity / negative regulation of Ras protein signal transduction / fructose 1,6-bisphosphate metabolic process / cellular response to magnesium ion / Gluconeogenesis / fructose metabolic process / fructose 6-phosphate metabolic process / monosaccharide binding / negative regulation of glycolytic process / regulation of gluconeogenesis / cellular hyperosmotic salinity response / AMP binding / cellular response to cAMP / gluconeogenesis / response to nutrient levels / negative regulation of cell growth / cellular response to xenobiotic stimulus / cellular response to insulin stimulus / RNA polymerase II-specific DNA-binding transcription factor binding / negative regulation of transcription by RNA polymerase II / extracellular exosome / metal ion binding / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Fructose-1,6-bisphosphatase / Fructose-1,6-bisphosphatase, active site / Fructose-1-6-bisphosphatase active site. / Fructose-1,6-bisphosphatase class 1 / Fructose-1-6-bisphosphatase class I, N-terminal / Fructose-1-6-bisphosphatase class 1, C-terminal / Fructose-1-6-bisphosphatase, N-terminal domain / Fructose-1-6-bisphosphatase, C-terminal domain
Similarity search - Domain/homology
Chem-0KI / 1,6-di-O-phosphono-beta-D-fructofuranose / Fructose-1,6-bisphosphatase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 Å
AuthorsWang, X.Y. / Zhou, J. / Xu, B.L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Discovery of Novel Indole Derivatives as Fructose-1,6-bisphosphatase Inhibitors and X-ray Cocrystal Structures Analysis.
Authors: Wang, X. / Zhao, R. / Ji, W. / Zhou, J. / Liu, Q. / Zhao, L. / Shen, Z. / Liu, S. / Xu, B.
History
DepositionJun 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fructose-1,6-bisphosphatase 1
B: Fructose-1,6-bisphosphatase 1
C: Fructose-1,6-bisphosphatase 1
D: Fructose-1,6-bisphosphatase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,09312
Polymers147,5504
Non-polymers2,5438
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area18700 Å2
ΔGint-93 kcal/mol
Surface area43040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.076, 143.329, 73.491
Angle α, β, γ (deg.)90.000, 108.140, 90.000
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein
Fructose-1,6-bisphosphatase 1 / FBPase 1 / D-fructose-1 / 6-bisphosphate 1-phosphohydrolase 1 / Liver FBPase


Mass: 36887.434 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FBP1, FBP / Production host: Escherichia coli (E. coli) / References: UniProt: P09467, fructose-bisphosphatase
#2: Chemical
ChemComp-0KI / 7-chloranyl-5-ethyl-3-(3-hydroxy-3-oxopropyl)-1H-indole-2-carboxylic acid


Mass: 295.718 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H14ClNO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Sugar
ChemComp-FBP / 1,6-di-O-phosphono-beta-D-fructofuranose / BETA-FRUCTOSE-1,6-DIPHOSPHATE / FRUCTOSE-1,6-BISPHOSPHATE / 1,6-di-O-phosphono-beta-D-fructose / 1,6-di-O-phosphono-D-fructose / 1,6-di-O-phosphono-fructose


Type: D-saccharide, beta linking / Mass: 340.116 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C6H14O12P2 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
b-D-Fruf1PO36PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 166 / 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: 2.32 Å3/Da / Density % sol: 46.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.2M Ammonium acetate, 0.1M HEPES, 20% PEG 3350, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97915 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.76→47.78 Å / Num. obs: 33781 / % possible obs: 99.4 % / Redundancy: 6.9 % / CC1/2: 0.996 / Rmerge(I) obs: 0.132 / Rpim(I) all: 0.054 / Rrim(I) all: 0.143 / Net I/σ(I): 13.6 / Num. measured all: 232384 / Scaling rejects: 82
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.76-2.8970.4693081644250.9560.1910.5074.798.5
9.15-47.786.30.0558629340.9980.0210.05428.197.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2FIE

2fie


Resolution: 2.76→47.67 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.905 / SU B: 14.279 / SU ML: 0.281 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.374 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2359 1717 5.1 %RANDOM
Rwork0.1923 ---
obs0.1946 32038 99.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 138.04 Å2 / Biso mean: 40.721 Å2 / Biso min: 13.96 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0 Å20.03 Å2
2--0.02 Å2-0 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 2.76→47.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9823 0 160 166 10149
Biso mean--42.79 32.17 -
Num. residues----1285
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01310160
X-RAY DIFFRACTIONr_bond_other_d0.0020.0179834
X-RAY DIFFRACTIONr_angle_refined_deg1.4041.66613753
X-RAY DIFFRACTIONr_angle_other_deg1.31.59522737
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.94151278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.01222.596443
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.561151782
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8081552
X-RAY DIFFRACTIONr_chiral_restr0.0670.21325
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211238
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022098
LS refinement shellResolution: 2.76→2.83 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.346 117 -
Rwork0.272 2324 -
obs--97.64 %

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