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- PDB-4rch: Discovery of 2-Pyridyl Ureas as Glucokinase Activators -

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Basic information

Entry
Database: PDB / ID: 4rch
TitleDiscovery of 2-Pyridyl Ureas as Glucokinase Activators
ComponentsGlucokinase
KeywordsTRANSFERASE
Function / homology
Function and homology information


Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / glucose sensor activity / mannokinase activity / regulation of potassium ion transport / hexokinase / glucose catabolic process / fructokinase activity / glucokinase activity / glucose 6-phosphate metabolic process / NADP+ metabolic process ...Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) / glucose sensor activity / mannokinase activity / regulation of potassium ion transport / hexokinase / glucose catabolic process / fructokinase activity / 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) / D-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 / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / response to glucose / regulation of insulin secretion / 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
Chem-3LZ / alpha-D-glucopyranose / Hexokinase-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsVoegtli, W. / Vigers, G.P.A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of 2-pyridylureas as glucokinase activators.
Authors: Hinklin, R.J. / Aicher, T.D. / Anderson, D.A. / Baer, B.R. / Boyd, S.A. / Condroski, K.R. / DeWolf, W.E. / Kraser, C.F. / McVean, M. / Rhodes, S.P. / Sturgis, H.L. / Voegtli, W.C. / Williams, L. / Houze, J.B.
History
DepositionSep 16, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 22, 2014Group: 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 1.3Sep 20, 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)53,5883
Polymers53,0261
Non-polymers5622
Water45025
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)80.116, 80.116, 321.807
Angle α, β, γ (deg.)90.00, 90.00, 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: 53026.219 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 / 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-3LZ / 1-{3-[(2-ethylpyridin-3-yl)oxy]-5-(pyridin-2-ylsulfanyl)pyridin-2-yl}-3-methylurea


Mass: 381.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19N5O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 2.81 Å3/Da / Density % sol: 56.25 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM Hepes, pH 7.0, 28% PEG 1500, 5% glycerol, 50 mM glucose, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 14, 2010 / Details: Rh coated flat mirror
RadiationMonochromator: Side scattering I-beam bent single crystal; asymmetric cut 4.9650 deg.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.3→29.19 Å / Num. all: 28458 / Num. obs: 28432 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 9.99 % / Rmerge(I) obs: 0.125 / Rsym value: 0.119 / Net I/σ(I): 8.08
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 10.42 % / Rmerge(I) obs: 0.285 / Mean I/σ(I) obs: 2.8 / Num. unique all: 4054 / Rsym value: 0.285 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREPphasing
REFMAC5.8.0049refinement
CrystalCleardata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4MLE

4mle


Resolution: 2.3→29.19 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.917 / SU B: 6.648 / SU ML: 0.162 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.288 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26748 1429 5 %RANDOM
Rwork0.23121 ---
obs0.23305 26901 99.83 %-
all-28454 --
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: 58.174 Å2
Baniso -1Baniso -2Baniso -3
1-1.02 Å20.51 Å2-0 Å2
2--1.02 Å20 Å2
3----3.3 Å2
Refinement stepCycle: LAST / Resolution: 2.3→29.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3505 0 39 25 3569
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193600
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3511.9774840
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7865447
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.00624.035171
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.40515659
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.9331530
X-RAY DIFFRACTIONr_chiral_restr0.0940.2533
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022708
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_it3.5475.5921791
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.2028.3762237
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.5515.9981805
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined8.80246.1595378
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: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.371 95 -
Rwork0.268 1954 -
obs--100 %

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