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- PDB-7ebh: Crystal structure of human pyruvate dehydrogenase kinase 2 in com... -

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Basic information

Entry
Database: PDB / ID: 7ebh
TitleCrystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 13
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
KeywordsTRANSFERASE / PDHK / KINASE INHIBITORS / FRAGMENT SCREENING / PDK1 / PDK2 / PDK3 / PDK4
Function / homology
Function and homology information


[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of ketone metabolic process / pyruvate dehydrogenase complex / regulation of pH / cellular response to nutrient / Signaling by Retinoic Acid / regulation of gluconeogenesis ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of ketone metabolic process / pyruvate dehydrogenase complex / regulation of pH / cellular response to nutrient / Signaling by Retinoic Acid / regulation of gluconeogenesis / intrinsic apoptotic signaling pathway by p53 class mediator / regulation of glucose metabolic process / regulation of calcium-mediated signaling / cellular response to reactive oxygen species / glucose metabolic process / insulin receptor signaling pathway / glucose homeostasis / protein kinase activity / mitochondrial matrix / protein homodimerization activity / mitochondrion / nucleoplasm / ATP binding / cytosol
Similarity search - Function
Branched-chain alpha-ketoacid dehydrogenase kinase/Pyruvate dehydrogenase kinase, N-terminal / Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain superfamily / PDK/BCKDK protein kinase / Mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase / Histidine kinase domain / Histidine kinase domain profile. / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily
Similarity search - Domain/homology
ACETATE ION / Chem-J0F / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 Å
AuthorsOrita, T. / Doi, S. / Iwanaga, T. / Adachi, T.
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Fragment-based lead discovery to identify novel inhibitors that target the ATP binding site of pyruvate dehydrogenase kinases.
Authors: Akaki, T. / Bessho, Y. / Ito, T. / Fujioka, S. / Ubukata, M. / Mori, G. / Yamanaka, K. / Orita, T. / Doi, S. / Iwanaga, T. / Ikegashira, K. / Hantani, Y. / Nakanishi, I. / Adachi, T.
History
DepositionMar 9, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _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: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2127
Polymers44,6481
Non-polymers5646
Water1,58588
1
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules

A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules


  • defined by author&software
  • Evidence: gel filtration, Protein production and purification refers "Biochemistry 2006, 45, 2, 402-415". i.e. PDB (2btz, 2bu2, 2bu5, 2bu6, 2bu7, and 2bu8) and "J Biol Chem. 2008;283(37):25305-25315". ...Evidence: gel filtration, Protein production and purification refers "Biochemistry 2006, 45, 2, 402-415". i.e. PDB (2btz, 2bu2, 2bu5, 2bu6, 2bu7, and 2bu8) and "J Biol Chem. 2008;283(37):25305-25315". i.e. PDB(3d2r, 2zkj)
  • 90.4 kDa, 2 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)90,42314
Polymers89,2952
Non-polymers1,12812
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_665-x+1,-y+1,z1
Buried area4730 Å2
ΔGint-32 kcal/mol
Surface area30110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.347, 109.347, 84.167
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Space group name HallP64
Symmetry operation#1: x,y,z
#2: x-y,x,z+2/3
#3: y,-x+y,z+1/3
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z

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Components

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Protein , 1 types, 1 molecules A

#1: Protein [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial / Pyruvate dehydrogenase kinase isoform 2 / PDH kinase 2 / PDKII


Mass: 44647.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK2, PDHK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase

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Non-polymers , 5 types, 94 molecules

#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-J0F / 5-bromanyl-2-methyl-6-propyl-7H-pyrrolo[2,3-d]pyrimidine


Mass: 254.126 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H12BrN3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.25 Å3/Da / Density % sol: 62.19 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 50 mM Na acetate pH 5.5, 100 mM magnesium chloride and 8% (v/v) isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.96→94.7 Å / Num. obs: 40300 / % possible obs: 98.7 % / Redundancy: 10.1 % / Biso Wilson estimate: 41.69 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.018 / Rrim(I) all: 0.059 / Net I/σ(I): 19.5
Reflection shellResolution: 1.96→2.02 Å / Redundancy: 10 % / Rmerge(I) obs: 1.015 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 2943 / CC1/2: 0.802 / Rpim(I) all: 0.333 / Rrim(I) all: 1.069 / % possible all: 97.7

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Processing

Software
NameVersionClassification
PHENIX1.19rc3_4028refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2btz

2btz


Resolution: 1.96→94.7 Å / SU ML: 0.2166 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.5776
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2023 2044 5.07 %
Rwork0.1987 38237 -
obs0.1988 40281 98.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.63 Å2
Refinement stepCycle: LAST / Resolution: 1.96→94.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2734 0 31 88 2853
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00482858
X-RAY DIFFRACTIONf_angle_d0.78613866
X-RAY DIFFRACTIONf_chiral_restr0.0475424
X-RAY DIFFRACTIONf_plane_restr0.0038495
X-RAY DIFFRACTIONf_dihedral_angle_d11.00281066
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.96-2.010.28071200.27672522X-RAY DIFFRACTION97.17
2.01-2.060.27181480.24782535X-RAY DIFFRACTION98.64
2.06-2.120.24371570.23862496X-RAY DIFFRACTION98.88
2.12-2.180.23731410.23582562X-RAY DIFFRACTION99.01
2.18-2.250.26011480.24952520X-RAY DIFFRACTION99.11
2.25-2.330.26441370.23232569X-RAY DIFFRACTION98.98
2.33-2.420.23661400.21662456X-RAY DIFFRACTION95.62
2.42-2.530.19391280.20272555X-RAY DIFFRACTION99.55
2.53-2.670.2371120.22192597X-RAY DIFFRACTION99.23
2.67-2.830.2291250.23122567X-RAY DIFFRACTION99.45
2.83-3.050.24341200.22952596X-RAY DIFFRACTION99.2
3.05-3.360.18441390.21172536X-RAY DIFFRACTION98.06
3.36-3.840.18871630.18962570X-RAY DIFFRACTION99.82
3.85-4.840.15281330.16292528X-RAY DIFFRACTION97.58
4.84-94.70.2041330.17632628X-RAY DIFFRACTION98.5
Refinement TLS params.Method: refined / Origin x: 46.7495288993 Å / Origin y: 45.6732922148 Å / Origin z: 72.4035994514 Å
111213212223313233
T0.312003104907 Å20.0527451423602 Å2-0.0567404627235 Å2-0.261615785756 Å2-0.01569520172 Å2--0.371561160382 Å2
L2.40051594806 °20.188323494113 °20.389851089509 °2-1.41504961927 °20.0876712180931 °2--1.70131384128 °2
S-0.0525165423557 Å °0.187275212823 Å °-0.0940190307906 Å °0.33736246104 Å °0.00987597066098 Å °-0.309841318643 Å °-0.0371344964933 Å °0.201652963628 Å °0.0104917247333 Å °
Refinement TLS groupSelection details: all

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