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- PDB-6e0i: Crystal structure of Glucokinase in complex with compound 72 -

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Basic information

Entry
Database: PDB / ID: 6e0i
TitleCrystal structure of Glucokinase in complex with compound 72
ComponentsGlucokinase
KeywordsTransferase/Transferase Inhibitor / Glucokinase / glucokinase activator / structure-aided design / structure-based design / type II diabetes / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / glucose sensor activity / mannokinase activity / hexokinase / glucose catabolic process / fructokinase activity / glucokinase activity / glucose 6-phosphate metabolic process / Regulation of Glucokinase by Glucokinase Regulatory Protein / Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) ...Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / glucose sensor activity / mannokinase activity / hexokinase / glucose catabolic process / fructokinase activity / glucokinase activity / glucose 6-phosphate metabolic process / Regulation of Glucokinase by Glucokinase Regulatory Protein / Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) / calcium ion import / D-glucose binding / cellular response to leptin stimulus / Glycolysis / canonical glycolysis / regulation of glycolytic process / Regulation of gene expression in beta cells / regulation of insulin secretion / response to glucose / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / intracellular glucose homeostasis / glycolytic process / positive regulation of insulin secretion / glucose metabolic process / glucose homeostasis / cellular response to insulin stimulus / mitochondrion / nucleoplasm / ATP binding / cytosol
Similarity search - Function
Hexokinase; domain 1 / Hexokinase; domain 1 - #20 / Hexokinase / Hexokinase, binding site / Hexokinase, N-terminal / Hexokinase, C-terminal / Hexokinase / Hexokinase / Hexokinase domain signature. / Hexokinase domain profile. ...Hexokinase; domain 1 / Hexokinase; domain 1 - #20 / Hexokinase / Hexokinase, binding site / Hexokinase, N-terminal / Hexokinase, C-terminal / Hexokinase / Hexokinase / Hexokinase domain signature. / Hexokinase domain profile. / ATPase, nucleotide binding domain / ATPase, nucleotide binding domain / Nucleotidyltransferase; domain 5 / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
alpha-D-glucopyranose / Chem-HKG / Hexokinase-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsHinklin, R.J. / Baer, B.R. / Boyd, S.A. / Chicarelli, M.D. / Condroski, K.R. / DeWolf, W.E. / Fischer, J. / Frank, M. / Hingorani, G.P. / Lee, P.A. ...Hinklin, R.J. / Baer, B.R. / Boyd, S.A. / Chicarelli, M.D. / Condroski, K.R. / DeWolf, W.E. / Fischer, J. / Frank, M. / Hingorani, G.P. / Lee, P.A. / Neitzel, N.A. / Pratt, S.A. / Singh, A. / Sullivan, F.X. / Turner, T. / Voegtli, W.C. / Wallace, E.M. / Williams, L. / Aicher, T.D.
CitationJournal: Bioorg.Med.Chem. / Year: 2020
Title: Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator.
Authors: Hinklin, R.J. / Baer, B.R. / Boyd, S.A. / Chicarelli, M.D. / Condroski, K.R. / DeWolf Jr., W.E. / Fischer, J. / Frank, M. / Hingorani, G.P. / Lee, P.A. / Neitzel, N.A. / Pratt, S.A. / Singh, ...Authors: Hinklin, R.J. / Baer, B.R. / Boyd, S.A. / Chicarelli, M.D. / Condroski, K.R. / DeWolf Jr., W.E. / Fischer, J. / Frank, M. / Hingorani, G.P. / Lee, P.A. / Neitzel, N.A. / Pratt, S.A. / Singh, A. / Sullivan, F.X. / Turner, T. / Voegtli, W.C. / Wallace, E.M. / Williams, L. / Aicher, T.D.
History
DepositionJul 6, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2020Group: Database references / Structure summary / Category: chem_comp / citation / citation_author
Item: _chem_comp.pdbx_synonyms / _chem_comp.type ..._chem_comp.pdbx_synonyms / _chem_comp.type / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,3034
Polymers51,5251
Non-polymers7783
Water5,891327
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.450, 85.340, 85.860
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Glucokinase / Hexokinase type IV / HK IV / Hexokinase-4 / HK4 / Hexokinase-D


Mass: 51525.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCK / Production host: Escherichia coli (E. coli) / References: UniProt: P35557, glucokinase
#2: Sugar ChemComp-GLC / alpha-D-glucopyranose / alpha-D-glucose / D-glucose / glucose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C6H12O6
IdentifierTypeProgram
DGlcpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-D-glucopyranoseCOMMON NAMEGMML 1.0
a-D-GlcpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-HKG / 1-{4-[5-({3-[(2-methylpyridin-3-yl)oxy]-5-[(pyridin-2-yl)sulfanyl]pyridin-2-yl}amino)-1,2,4-thiadiazol-3-yl]piperidin-1 -yl}ethan-1-one / AR453588


Mass: 519.642 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25N7O2S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 327 / 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: 49.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1M Hepes pH7.5, 28% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Dec 23, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→27.13 Å / Num. obs: 37672 / % possible obs: 96.5 % / Redundancy: 6.8 % / Net I/σ(I): 8.3
Reflection shellResolution: 1.9→2 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.9→27.13 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.924 / SU B: 3.105 / SU ML: 0.092 / Cross valid method: THROUGHOUT / ESU R: 0.167 / ESU R Free: 0.149
RfactorNum. reflection% reflectionSelection details
Rfree0.22873 2259 6 %RANDOM
Rwork0.19134 ---
obs0.19357 35363 96.08 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 22.644 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å2-0 Å2-0 Å2
2---0.66 Å20 Å2
3---0.59 Å2
Refinement stepCycle: 1 / Resolution: 1.9→27.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3516 0 52 327 3895
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193620
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.181.9844860
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3635445
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.39823.86171
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.00915671
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5941532
X-RAY DIFFRACTIONr_chiral_restr0.0790.2536
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022703
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_it0.7432.1091789
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.3183.1552231
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.9212.2731831
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined3.79129.5595691
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: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.255 131 -
Rwork0.225 1982 -
obs--74.59 %

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