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- PDB-4iwv: Crystals structure of Human Glucokinase in complex with small mol... -

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Basic information

Entry
Database: PDB / ID: 4iwv
TitleCrystals structure of Human Glucokinase in complex with small molecule activator
ComponentsGlucokinase isoform 3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Allosteric Site / Catalysis / Enzyme Activation / Gene Expression Regulation / Glucokinase / Glucose / Homeostasis / Humans / Hypoglycemia / Kinetics / Biological / Models / Molecular / Mutation / Protein Conformation / Scattering / Radiation / X-Rays / TRANSFERASE-TRANSFERASE INHIBITOR 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 / Regulation of Glucokinase by Glucokinase Regulatory Protein / Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) / 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 / Hexokinase domain profile. / Hexokinase domain signature. / Hexokinase / Hexokinase / Hexokinase, C-terminal / Hexokinase, N-terminal ...Hexokinase-4, chordate / Hexokinase; domain 1 / Hexokinase; domain 1 - #20 / Hexokinase / Hexokinase domain profile. / Hexokinase domain signature. / Hexokinase / Hexokinase / Hexokinase, C-terminal / Hexokinase, N-terminal / Hexokinase, binding site / 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-1J9 / alpha-D-glucopyranose / Hexokinase-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsOgg, D.J. / Hargreaves, D. / Gerhardt, S. / Flavell, L. / McAlister, M.
CitationJournal: To be Published
Title: Optimising pharmacokinetics of glucokinase activators with matched triplicate design sets the discovery of AZD3651 and AZD9485
Authors: Waring, M.J. / Bennett, S.N. / Boyd, S. / Campbell, L. / Davies, R.D.M. / Ogg, D.J. / Hargreaves, D. / Martin, N.G. / Robb, G. / Wilkinson, S. / MacPaul, P. / Wood, J.M.
History
DepositionJan 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucokinase isoform 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,5004
Polymers50,8081
Non-polymers6923
Water2,720151
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)77.938, 77.938, 85.350
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein Glucokinase isoform 3 / Hexokinase type IV / HK IV / Hexokinase-4 / HK4 / Hexokinase-D


Mass: 50807.680 Da / Num. of mol.: 1 / Fragment: GLUCOKINASE / Mutation: E27A E28A E51A E52A
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: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: 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
#4: Chemical ChemComp-1J9 / (2S)-2-{[1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}-N-(5-chloropyridin-2-yl)-3-(2-hydroxyethoxy)propanamide


Mass: 489.311 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18Cl2N6O4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.55 Å3/Da / Density % sol: 51.78 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 20% glucose, 10-18% Peg8000, 200mM sodium acetate, MMT 100mM pH7.0-8.5, pH 7.4, VAPOR DIFFUSION, SITTING DROP, temperature 292K
PH range: 7.0-8.5

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Sep 9, 2008 / Details: Osmic VariMax HF mirrors
RadiationMonochromator: Graded, multilayer confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→55 Å / Num. all: 29845 / Num. obs: 28409 / % possible obs: 95.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 2.43 % / Biso Wilson estimate: 27.84 Å2 / Rmerge(I) obs: 0.052 / Net I/σ(I): 10.6
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.275 / Mean I/σ(I) obs: 2 / Num. unique all: 2825 / % possible all: 73.4

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
REFMAC5.7.0032refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1V4S
Resolution: 2.1→37.46 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.911 / SU B: 11.438 / SU ML: 0.155 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.239 / ESU R Free: 0.201 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24982 1450 5.1 %RANDOM
Rwork0.19897 ---
all0.20165 29845 --
obs0.20165 26853 94.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 44.59 Å2
Baniso -1Baniso -2Baniso -3
1--1.08 Å20 Å2-0 Å2
2---1.08 Å2-0 Å2
3---2.16 Å2
Refinement stepCycle: LAST / Resolution: 2.1→37.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3457 0 46 151 3654
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193593
X-RAY DIFFRACTIONr_bond_other_d0.0010.023355
X-RAY DIFFRACTIONr_angle_refined_deg1.8541.9864830
X-RAY DIFFRACTIONr_angle_other_deg0.8883.0017716
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7875440
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.70323.855166
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.66215647
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4551530
X-RAY DIFFRACTIONr_chiral_restr0.110.2529
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024127
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02799
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.262 63 -
Rwork0.261 1503 -
obs--71.41 %
Refinement TLS params.Method: refined / Origin x: 64.8241 Å / Origin y: 24.3921 Å / Origin z: -0.0188 Å
111213212223313233
T0.0361 Å2-0.007 Å20.0158 Å2-0.0252 Å2-0.0221 Å2--0.0495 Å2
L0.9171 °2-0.5735 °2-0.093 °2-0.4236 °20.1569 °2--0.1685 °2
S-0.0293 Å °-0.0831 Å °0.1469 Å °0.0322 Å °0.0618 Å °-0.1137 Å °0.0307 Å °0.0016 Å °-0.0325 Å °

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