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- PDB-7t79: CRYSTAL STRUCTURE OF GLUCOKINASE (HEXOKINASE 4) COMPLEXED WITH LI... -

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Basic information

Entry
Database: PDB / ID: 7t79
TitleCRYSTAL STRUCTURE OF GLUCOKINASE (HEXOKINASE 4) COMPLEXED WITH LIGAND AKA DIETHYL {[3-(3-{[5-(AZETIDINE-1-CARBON YL)PYRAZIN-2-YL]OXY}-5-(PROPAN-2-YLOXY)BENZAMIDO)-1H- PYRAZOL-1-YL]METHYL}PHOSPHONATE
ComponentsIsoform 2 of Hexokinase-4
KeywordsTRANSFERASE
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 / Hexokinase, binding site / Hexokinase, N-terminal / Hexokinase, C-terminal / Hexokinase / Hexokinase / Hexokinase domain signature. / Hexokinase domain profile. / ATPase, nucleotide binding domain
Similarity search - Domain/homology
Chem-G1S / alpha-D-glucopyranose / Hexokinase-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsMuckelbauer, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1 H -pyrazol-1-yl)methyl)phosphonate (BMS-820132).
Authors: Shi, Y. / Wang, Y. / Meng, W. / Brigance, R.P. / Ryono, D.E. / Bolton, S. / Zhang, H. / Chen, S. / Smirk, R. / Tao, S. / Tino, J.A. / Williams, K.N. / Sulsky, R. / Nielsen, L. / Ellsworth, B. ...Authors: Shi, Y. / Wang, Y. / Meng, W. / Brigance, R.P. / Ryono, D.E. / Bolton, S. / Zhang, H. / Chen, S. / Smirk, R. / Tao, S. / Tino, J.A. / Williams, K.N. / Sulsky, R. / Nielsen, L. / Ellsworth, B. / Wong, M.K.Y. / Sun, J.H. / Leith, L.W. / Sun, D. / Wu, D.R. / Gupta, A. / Rampulla, R. / Mathur, A. / Chen, B.C. / Wang, A. / Fuentes-Catanio, H.G. / Kunselman, L. / Cap, M. / Zalaznick, J. / Ma, X. / Liu, H. / Taylor, J.R. / Zebo, R. / Jones, B. / Kalinowski, S. / Swartz, J. / Staal, A. / O'Malley, K. / Kopcho, L. / Muckelbauer, J.K. / Krystek Jr., S.R. / Spronk, S.A. / Marcinkeviciene, J. / Everlof, G. / Chen, X.Q. / Xu, C. / Li, Y.X. / Langish, R.A. / Yang, Y. / Wang, Q. / Behnia, K. / Fura, A. / Janovitz, E.B. / Pannacciulli, N. / Griffen, S. / Zinker, B.A. / Krupinski, J. / Kirby, M. / Whaley, J. / Zahler, R. / Barrish, J.C. / Robl, J.A. / Cheng, P.T.W.
History
DepositionDec 14, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Feb 28, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2 of Hexokinase-4
B: Isoform 2 of Hexokinase-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,9046
Polymers104,3992
Non-polymers1,5054
Water1,47782
1
A: Isoform 2 of Hexokinase-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,9523
Polymers52,1991
Non-polymers7532
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Isoform 2 of Hexokinase-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,9523
Polymers52,1991
Non-polymers7532
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)84.510, 102.080, 130.980
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 Isoform 2 of Hexokinase-4 / HK4 / Glucokinase / Hexokinase type IV / HK IV / Hexokinase-D


Mass: 52199.309 Da / Num. of mol.: 2
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, hexokinase
#2: Chemical ChemComp-G1S / diethyl {[3-(3-{[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy}-5-[(propan-2-yl)oxy]benzamido)-1H-pyrazol-1-yl]methyl}phosphonate


Mass: 572.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H33N6O7P / Feature type: SUBJECT OF INVESTIGATION
#3: 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.: 2 / Source method: obtained synthetically / 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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 82 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.71 Å3/Da / Density % sol: 54.54 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: PEG 600, Hepes pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.979 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Feb 8, 2012 / Details: ???
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.4→47.56 Å / Num. obs: 44988 / % possible obs: 99.9 % / Redundancy: 9.7 % / Biso Wilson estimate: 60.29 Å2 / Rmerge F obs: 0.073 / Rrim(I) all: 0.088 / Rsym value: 0.084 / Χ2: 0.964 / Net I/σ(I): 17.3 / Num. measured all: 436740 / Scaling rejects: 10
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 10.7 % / Mean I/σ(I) obs: 3.4 / Num. unique obs: 3269 / Rsym value: 0.742 / % possible all: 100

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Processing

Software
NameVersionClassification
XSCALEdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→47.56 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.91 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.304 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.299 / SU Rfree Blow DPI: 0.23 / SU Rfree Cruickshank DPI: 0.233
RfactorNum. reflection% reflectionSelection details
Rfree0.254 2273 5.05 %RANDOM
Rwork0.211 ---
obs0.213 44987 100 %-
Displacement parametersBiso max: 116.13 Å2 / Biso mean: 53.4 Å2 / Biso min: 23.76 Å2
Baniso -1Baniso -2Baniso -3
1-0.6444 Å20 Å20 Å2
2---0.8065 Å20 Å2
3---0.1621 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.4→47.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6441 0 104 82 6627
Biso mean--45 45.75 -
Num. residues----889
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2248SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes137HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1073HARMONIC5
X-RAY DIFFRACTIONt_it6717HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion897SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7891SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6717HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg9157HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion16.81
LS refinement shellResolution: 2.4→2.46 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 166 5.09 %
Rwork0.251 3094 -
all0.253 3260 -
obs--99.94 %

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