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- PDB-2y5k: Orally active aminopyridines as inhibitors of tetrameric fructose... -

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Basic information

Entry
Database: PDB / ID: 2y5k
TitleOrally active aminopyridines as inhibitors of tetrameric fructose 1,6- bisphosphatase
ComponentsFRUCTOSE-1,6-BISPHOSPHATASE 1
KeywordsHYDROLASE
Function / homology
Function and homology information


cellular response to raffinose / cellular hypotonic salinity response / cellular response to phorbol 13-acetate 12-myristate / fructose-bisphosphatase / fructose 1,6-bisphosphate 1-phosphatase activity / cellular response to magnesium ion / fructose 1,6-bisphosphate metabolic process / negative regulation of Ras protein signal transduction / Gluconeogenesis / monosaccharide binding ...cellular response to raffinose / cellular hypotonic salinity response / cellular response to phorbol 13-acetate 12-myristate / fructose-bisphosphatase / fructose 1,6-bisphosphate 1-phosphatase activity / cellular response to magnesium ion / fructose 1,6-bisphosphate metabolic process / negative regulation of Ras protein signal transduction / Gluconeogenesis / monosaccharide binding / fructose metabolic process / fructose 6-phosphate metabolic process / negative regulation of glycolytic process / cellular hyperosmotic salinity response / regulation of gluconeogenesis / dephosphorylation / AMP binding / cellular response to cAMP / gluconeogenesis / response to nutrient levels / negative regulation of cell growth / cellular response to insulin stimulus / cellular response to xenobiotic 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 / cytosol / cytoplasm
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 / D-Maltodextrin-Binding Protein; domain 2 - #80 / Fructose-1,6-Bisphosphatase, subunit A, domain 1 ...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 / D-Maltodextrin-Binding Protein; domain 2 - #80 / Fructose-1,6-Bisphosphatase, subunit A, domain 1 / Fructose-1,6-Bisphosphatase; Chain A, domain 1 / D-Maltodextrin-Binding Protein; domain 2 / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-YCU / Fructose-1,6-bisphosphatase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsRuf, A. / Hebeisen, P. / Haap, W. / Kuhn, B. / Mohr, P. / Wessel, H.P. / Zutter, U. / Kirchner, S. / Benz, J. / Joseph, C. ...Ruf, A. / Hebeisen, P. / Haap, W. / Kuhn, B. / Mohr, P. / Wessel, H.P. / Zutter, U. / Kirchner, S. / Benz, J. / Joseph, C. / Alvarez-Sanchez, R. / Gubler, M. / Schott, B. / Benardeau, A. / Tozzo, E. / Kitas, E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Orally Active Aminopyridines as Inhibitors of Tetrameric Fructose-1,6-Bisphosphatase.
Authors: Hebeisen, P. / Haap, W. / Kuhn, B. / Mohr, P. / Wessel, H.P. / Zutter, U. / Kirchner, S. / Ruf, A. / Benz, J. / Joseph, C. / Alvarez-Sanchez, R. / Gubler, M. / Schott, B. / Benardeau, A. / Tozzo, E. / Kitas, E.
History
DepositionJan 14, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 18, 2011Provider: repository / Type: Initial release
Revision 1.1May 26, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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: 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)149,2688
Polymers147,4384
Non-polymers1,8304
Water18,0691003
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15900 Å2
ΔGint-80.3 kcal/mol
Surface area43890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.136, 82.784, 276.604
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C
41D
12A
22B
32C
42D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1115A1 - 250
2115B1 - 250
3115C1 - 250
4115D1 - 250
1124A1336
2124B1336
3124C1336
4124D1336

NCS ensembles :
ID
1
2

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Components

#1: Protein
FRUCTOSE-1,6-BISPHOSPHATASE 1 / D-FRUCTOSE-1 / 6-BISPHOSPHATE 1-PHOSPHOHYDROLASE 1 / FBPASE 1


Mass: 36859.418 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Tissue: LIVER / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P09467, fructose-bisphosphatase
#2: Chemical
ChemComp-YCU / 1-[5-(2-METHOXYETHYL)-4-METHYL-THIOPHEN-2-YL]SULFONYL-3-[4-METHOXY-6-(METHYLCARBAMOYLAMINO)PYRIDIN-2-YL]UREA / RO5207315


Mass: 457.524 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H23N5O6S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1003 / 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: 2.61 Å3/Da / Density % sol: 52.81 % / Description: NONE
Crystal growDetails: RESERVOIR: 0.1M HEPES, PH 7.0, 0.1 M AMMONIUM ACETATE, 12% PEG 3350.

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1
DetectorType: MARRESEARCH / Detector: CCD / Date: May 22, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.06→142 Å / Num. obs: 87553 / % possible obs: 90.8 % / Observed criterion σ(I): -10 / Redundancy: 5.97 % / Biso Wilson estimate: 0.226 Å2 / Rmerge(I) obs: 0.15 / Net I/σ(I): 8.39
Reflection shellResolution: 2.06→2.19 Å / Redundancy: 3.42 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 3.45 / % possible all: 51.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2VT5

2vt5


Resolution: 2.1→29.48 Å / Cor.coef. Fo:Fc: 0.888 / Cor.coef. Fo:Fc free: 0.836 / SU B: 6.615 / SU ML: 0.182 / Cross valid method: THROUGHOUT / ESU R: 0.276 / ESU R Free: 0.231 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.29625 4326 4.9 %RANDOM
Rwork0.24405 ---
obs0.24663 83227 96.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.749 Å2
Baniso -1Baniso -2Baniso -3
1-0.64 Å20 Å20 Å2
2---0.61 Å20 Å2
3----0.03 Å2
Refinement stepCycle: LAST / Resolution: 2.1→29.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9729 0 120 1003 10852
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.02210025
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3572.00313544
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.01351263
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.85624.375384
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.068151777
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9431548
X-RAY DIFFRACTIONr_chiral_restr0.0870.21532
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.027408
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2120.25712
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3060.26916
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1960.21126
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1930.252
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2250.227
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6011.56457
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.01210153
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.60934004
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.4414.53391
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11A928medium positional0.210.5
12B928medium positional0.270.5
13C928medium positional0.240.5
14D928medium positional0.240.5
21A30medium positional0.170.5
22B30medium positional0.180.5
23C30medium positional0.180.5
24D30medium positional0.280.5
11A835loose positional0.565
12B835loose positional0.635
13C835loose positional0.685
14D835loose positional0.645
11A928medium thermal0.842
12B928medium thermal0.672
13C928medium thermal0.682
14D928medium thermal0.812
21A30medium thermal0.652
22B30medium thermal0.572
23C30medium thermal0.582
24D30medium thermal0.822
11A835loose thermal1.8310
12B835loose thermal1.5310
13C835loose thermal1.6310
14D835loose thermal1.9510
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 212 -
Rwork0.245 4386 -
obs--69.51 %

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