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- PDB-3imx: Crystal Structure of human glucokinase in complex with a syntheti... -

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Basic information

Entry
Database: PDB / ID: 3imx
TitleCrystal Structure of human glucokinase in complex with a synthetic activator
ComponentsGlucokinase
KeywordsTRANSFERASE / Sugar kinase / ATP-binding / Glycolysis / Kinase / Nucleotide-binding
Function / homology
Function and homology information


hexose metabolic process / Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / mannokinase activity / glucose sensor activity / regulation of potassium ion transport / Transferases; Transferring phosphorus-containing groups; Phosphotransferases with an alcohol group as acceptor / hexokinase / fructokinase activity / carbohydrate phosphorylation / glucokinase activity ...hexose metabolic process / Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / mannokinase activity / glucose sensor activity / regulation of potassium ion transport / Transferases; Transferring phosphorus-containing groups; Phosphotransferases with an alcohol group as acceptor / hexokinase / fructokinase activity / carbohydrate phosphorylation / glucokinase activity / glucose catabolic process / glucose 6-phosphate metabolic process / Regulation of Glucokinase by Glucokinase Regulatory Protein / Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) / NADP metabolic process / glucose binding / cellular response to leptin stimulus / calcium ion import / canonical glycolysis / Glycolysis / regulation of glycolytic process / intracellular glucose homeostasis / Regulation of gene expression in beta cells / regulation of insulin secretion / positive regulation of glycogen biosynthetic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / response to glucose / glycolytic process / positive regulation of insulin secretion / 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 / Hexokinase, binding site / Hexokinase, N-terminal / Hexokinase, C-terminal / Hexokinase / Hexokinase / Hexokinase domain signature. ...Hexokinase-4, chordate / 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
Chem-B84 / alpha-D-glucopyranose / Hexokinase-4 / Phosphotransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsStams, T. / Vash, B.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.
Authors: Bebernitz, G.R. / Beaulieu, V. / Dale, B.A. / Deacon, R. / Duttaroy, A. / Gao, J. / Grondine, M.S. / Gupta, R.C. / Kakmak, M. / Kavana, M. / Kirman, L.C. / Liang, J. / Maniara, W.M. / ...Authors: Bebernitz, G.R. / Beaulieu, V. / Dale, B.A. / Deacon, R. / Duttaroy, A. / Gao, J. / Grondine, M.S. / Gupta, R.C. / Kakmak, M. / Kavana, M. / Kirman, L.C. / Liang, J. / Maniara, W.M. / Munshi, S. / Nadkarni, S.S. / Schuster, H.F. / Stams, T. / St Denny, I. / Taslimi, P.M. / Vash, B. / Caplan, S.L.
History
DepositionAug 11, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Jul 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
Revision 1.4Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)51,6564
Polymers50,9091
Non-polymers7473
Water4,972276
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.500, 90.300, 116.200
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Glucokinase / / Hexokinase 4 / maturity onset diabetes of the young 2 / isoform CRA_b


Mass: 50908.797 Da / Num. of mol.: 1 / Fragment: residues 16-465
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCK, hCG_1745191, tcag7.801 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q53Y25, UniProt: P35557*PLUS
#2: Sugar ChemComp-GLC / alpha-D-glucopyranose / alpha-D-glucose / D-glucose / 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-B84 / (2R)-3-cyclopentyl-N-(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)-2-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}propanamide


Mass: 543.701 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H33N5O4S2
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 276 / 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: 2.34 Å3/Da / Density % sol: 47.54 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: PROTEIN: 10MG/ML IN 20MM TRIS PH 7.5, 50MM NACL, 5MM TCEP, 20MM GLUCOSE 300UM LBX192 WELL: 4C 100MM HEPES PH 6.0 20% PEG 3350 200MM NACL CRYO: WELL PLUS 20% GLYCEROL + 100UM LBX192, VAPOR ...Details: PROTEIN: 10MG/ML IN 20MM TRIS PH 7.5, 50MM NACL, 5MM TCEP, 20MM GLUCOSE 300UM LBX192 WELL: 4C 100MM HEPES PH 6.0 20% PEG 3350 200MM NACL CRYO: WELL PLUS 20% GLYCEROL + 100UM LBX192, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: May 1, 2005 / Details: Varimax
RadiationMonochromator: Varimax optics / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 32450 / % possible obs: 96.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5 % / Rmerge(I) obs: 0.106 / Χ2: 1.119 / Net I/σ(I): 11.8
Reflection shellResolution: 2→2.07 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.413 / Num. unique all: 2703 / Χ2: 1.352 / % possible all: 82.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_RTP

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER1.2phasing
CNSrefinement
PDB_EXTRACT3.005data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNX2002refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1V4S

1v4s


Resolution: 2→29.49 Å / Rfactor Rfree error: 0.007 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.841 / Data cutoff high absF: 1397300 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.245 1410 5 %RANDOM
Rwork0.195 ---
obs-28292 85.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 47.207 Å2 / ksol: 0.354 e/Å3
Displacement parametersBiso max: 79.37 Å2 / Biso mean: 28.986 Å2 / Biso min: 10.93 Å2
Baniso -1Baniso -2Baniso -3
1--0.58 Å20 Å20 Å2
2--8.16 Å20 Å2
3----7.58 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.23 Å0.31 Å
Refinement stepCycle: LAST / Resolution: 2→29.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3493 0 50 276 3819
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_improper_angle_d0.89
X-RAY DIFFRACTIONc_mcbond_it1.461.5
X-RAY DIFFRACTIONc_mcangle_it2.232
X-RAY DIFFRACTIONc_scbond_it2.362
X-RAY DIFFRACTIONc_scangle_it3.452.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.275 182 5.1 %
Rwork0.23 3405 -
all-3587 -
obs--66.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paraprotein.top
X-RAY DIFFRACTION2ion.paramion.top
X-RAY DIFFRACTION3water.paramlbx192.top
X-RAY DIFFRACTION4lbx192.parwater.top
X-RAY DIFFRACTION5glucose.parglucose.top

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