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- PDB-4ise: Human glucokinase in complex with novel activator (2S)-3-cyclohex... -

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Basic information

Entry
Database: PDB / ID: 4ise
TitleHuman glucokinase in complex with novel activator (2S)-3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(1,3-thiazol-2-yl)propanamide
ComponentsGlucokinase
KeywordsTRANSFERASE/TRANSFERASE ACTIVATOR / transferase/activator activity / glucose conversion to G6P / phosphorylation / TRANSFERASE-TRANSFERASE ACTIVATOR complex
Function / homology
Function and homology information


Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / detection of glucose / mannokinase activity / regulation of potassium ion transport / hexokinase / fructokinase activity / carbohydrate phosphorylation / glucokinase activity / glucose 6-phosphate metabolic process / NADP metabolic process ...Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / detection of glucose / mannokinase activity / regulation of potassium ion transport / hexokinase / fructokinase activity / carbohydrate phosphorylation / glucokinase activity / glucose 6-phosphate metabolic process / NADP metabolic process / Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) / Regulation of Glucokinase by Glucokinase Regulatory Protein / calcium ion import / cellular response to leptin stimulus / glucose binding / canonical glycolysis / regulation of glycolytic process / Glycolysis / cellular glucose homeostasis / Regulation of gene expression in beta cells / regulation of insulin secretion / positive regulation of insulin secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / glycolytic process / cellular response to insulin stimulus / glucose metabolic process / glucose homeostasis / mitochondrion / nucleoplasm / ATP binding / cytosol
Similarity search - Function
Hexokinase-4, chordate / Hexokinase; domain 1 / Hexokinase; domain 1 - #20 / Hexokinase, binding site / Hexokinase domain signature. / Hexokinase / Hexokinase, C-terminal / Hexokinase, N-terminal / Hexokinase / Hexokinase ...Hexokinase-4, chordate / Hexokinase; domain 1 / Hexokinase; domain 1 - #20 / Hexokinase, binding site / Hexokinase domain signature. / Hexokinase / Hexokinase, C-terminal / Hexokinase, N-terminal / Hexokinase / Hexokinase / 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
Chem-1FW / alpha-D-glucopyranose / IODIDE ION / Hexokinase-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 1.78 Å
AuthorsHosfield, D. / Skene, R.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Design, synthesis and SAR of novel glucokinase activators.
Authors: Cheruvallath, Z.S. / Gwaltney, S.L. / Sabat, M. / Tang, M. / Feng, J. / Wang, H. / Miura, J. / Guntupalli, P. / Jennings, A. / Hosfield, D. / Lee, B. / Wu, Y.
History
DepositionJan 16, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2013Group: Database references
Revision 1.2Jul 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_ref_seq_dif / 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 / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glucokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,1004
Polymers51,3931
Non-polymers7083
Water5,549308
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.483, 77.646, 119.274
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: 51392.527 Da / Num. of mol.: 1 / Fragment: UNP residues 16-465
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCK, HXK4 Isoform II / Plasmid: pFLAG-CTC / Production host: Escherichia coli (E. coli) / Strain (production host): DH5[alpha] / References: UniProt: P35557, glucokinase
#2: Sugar ChemComp-GLC / alpha-D-glucopyranose / 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-1FW / (2S)-3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(1,3-thiazol-2-yl)propanamide


Mass: 400.470 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21FN4O2S
#4: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.23 Å3/Da / Density % sol: 44.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 15% PEG3350, 200 mM ammonium iodide, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 20, 2006
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.78→50 Å / Num. all: 44990 / Num. obs: 41700 / % possible obs: 97.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1
Reflection shellResolution: 1.78→1.84 Å / % possible all: 90.7

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.7.0025refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MIR / Resolution: 1.78→45.64 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.932 / SU B: 5.725 / SU ML: 0.081 / Cross valid method: THROUGHOUT / ESU R: 0.135 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.22695 2205 5 %RANDOM
Rwork0.19851 ---
obs0.19989 41700 97.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.276 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0.02 Å20 Å2
3----0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.78→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3337 0 41 308 3686
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0193467
X-RAY DIFFRACTIONr_bond_other_d0.0010.023319
X-RAY DIFFRACTIONr_angle_refined_deg1.0611.9834661
X-RAY DIFFRACTIONr_angle_other_deg0.7437658
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0145423
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.32923.963164
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.1215647
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5961530
X-RAY DIFFRACTIONr_chiral_restr0.0560.2523
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023870
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02777
LS refinement shellResolution: 1.78→1.825 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 147 -
Rwork0.269 2746 -
obs--88.82 %
Refinement TLS params.Method: refined / Origin x: 4.5697 Å / Origin y: 46.4695 Å / Origin z: 38.9077 Å
111213212223313233
T0.0175 Å2-0.0008 Å2-0.0092 Å2-0.0184 Å2-0.0109 Å2--0.0137 Å2
L0.4712 °2-0.0722 °2-0.2735 °2-0.3132 °20.0067 °2--0.3249 °2
S0.0002 Å °0.0221 Å °-0.0401 Å °-0.054 Å °-0.0144 Å °0.0353 Å °0.034 Å °-0.0386 Å °0.0142 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A9 - 465
2X-RAY DIFFRACTION1A500 - 502
3X-RAY DIFFRACTION1A601 - 908

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