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- PDB-4mle: Human Glucokinase in Complex with Novel Amino Thiazole Activator -

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Basic information

Entry
Database: PDB / ID: 4mle
TitleHuman Glucokinase in Complex with Novel Amino Thiazole Activator
ComponentsGlucokinase
KeywordsTRANSFERASE/TRANSFERASE ACTIVATOR / sugar kinase / allosteric activator / small molecule / TRANSFERASE-TRANSFERASE ACTIVATOR complex
Function / homology
Function and homology information


Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / mannokinase activity / glucose sensor activity / regulation of potassium ion transport / hexokinase / fructokinase activity / carbohydrate phosphorylation / glucokinase activity / glucose catabolic process / glucose 6-phosphate metabolic process ...Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / mannokinase activity / glucose sensor activity / regulation of potassium ion transport / 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; 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-VO1 / Hexokinase-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsVoegtli, W.C.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Identification of a New Class of Glucokinase Activators through Structure-Based Design.
Authors: Hinklin, R.J. / Boyd, S.A. / Chicarelli, M.J. / Condroski, K.R. / Dewolf, W.E. / Lee, P.A. / Lee, W. / Singh, A. / Thomas, L. / Voegtli, W.C. / Williams, L. / Aicher, T.D.
History
DepositionSep 6, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 23, 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
Revision 1.3Feb 28, 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)51,4873
Polymers51,0091
Non-polymers4782
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)79.320, 79.320, 320.210
Angle α, β, γ (deg.)90.00, 90.000, 120.00
Int Tables number179
Space group name H-MP6522

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Components

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


Mass: 51008.996 Da / Num. of mol.: 1 / Fragment: SEE REMARK 999
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCK / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P35557, glucokinase
#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-VO1 / 3-(benzyloxy)-N-(4-methyl-1,3-thiazol-2-yl)pyridin-2-amine


Mass: 297.375 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N3OS
Sequence detailsPROTEIN CONSTRUCT IS RESIDUES 12-465 OF ISOFORM 2 (UNP P35557-2).

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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: 2.85 Å3/Da / Density % sol: 56.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: PEG1500, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. all: 19343 / Num. obs: 18608 / % possible obs: 96.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.2 % / Rmerge(I) obs: 0.043 / Net I/σ(I): 12.1
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.305 / Mean I/σ(I) obs: 2.6 / % possible all: 89

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Processing

Software
NameClassification
CrystalCleardata collection
CNSrefinement
MOSFLMdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→30 Å / Occupancy max: 1 / Occupancy min: 1 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.289 1087 5.6 %RANDOM
Rwork0.2423 17481 --
all-19387 --
obs-18568 95.8 %-
Displacement parametersBiso max: 110.15 Å2 / Biso mean: 56.893 Å2 / Biso min: 18.02 Å2
Baniso -1Baniso -2Baniso -3
1-0.021 Å2-0.345 Å20 Å2
2--0.021 Å20 Å2
3----0.041 Å2
Refinement stepCycle: LAST / Resolution: 2.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3505 0 33 0 3538
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.065
X-RAY DIFFRACTIONc_angle_deg1.27
X-RAY DIFFRACTIONc_mcbond_it1.5231.5
X-RAY DIFFRACTIONc_scbond_it2.1362
X-RAY DIFFRACTIONc_mcangle_it2.6512
X-RAY DIFFRACTIONc_scangle_it3.2872.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2dna-rna_rep.param
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5ligands.par

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