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- PDB-7ebg: Crystal structure of human pyruvate dehydrogenase kinase 4 in com... -

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Basic information

Entry
Database: PDB / ID: 7ebg
TitleCrystal structure of human pyruvate dehydrogenase kinase 4 in complex with compound 7
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
KeywordsTRANSFERASE / PDHK / KINASE INHIBITORS / FRAGMENT SCREENING / PDK1 / PDK2 / PDK3 / PDK4
Function / homology
Function and homology information


[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of fatty acid oxidation / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of pyruvate decarboxylation to acetyl-CoA / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of fatty acid biosynthetic process / regulation of ketone metabolic process / regulation of pH / cellular response to fatty acid / regulation of bone resorption ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of fatty acid oxidation / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of pyruvate decarboxylation to acetyl-CoA / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of fatty acid biosynthetic process / regulation of ketone metabolic process / regulation of pH / cellular response to fatty acid / regulation of bone resorption / Signaling by Retinoic Acid / response to starvation / regulation of glucose metabolic process / negative regulation of anoikis / reactive oxygen species metabolic process / cellular response to starvation / insulin receptor signaling pathway / glucose homeostasis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / protein kinase activity / mitochondrial matrix / mitochondrion / ATP binding
Similarity search - Function
Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain / 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 / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Histidine kinase domain / Histidine kinase domain profile. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 ...Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain / 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 / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Histidine kinase domain / Histidine kinase domain profile. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Up-down Bundle / 2-Layer Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / 3,3-dimethyl-7-(methylamino)-1H-indol-2-one / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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

Downloads & links

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Assembly

Deposited unit
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
B: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,1288
Polymers91,1982
Non-polymers9306
Water3,135174
1


  • Idetical with deposited unit
  • 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)
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4490 Å2
ΔGint-89 kcal/mol
Surface area28290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.965, 67.441, 78.605
Angle α, β, γ (deg.)90.000, 101.185, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial / Pyruvate dehydrogenase kinase isoform 4


Mass: 45598.879 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK4, PDHK4 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q16654, [pyruvate dehydrogenase (acetyl-transferring)] kinase

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Non-polymers , 5 types, 180 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-J0L / 3,3-dimethyl-7-(methylamino)-1H-indol-2-one


Mass: 190.242 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H14N2O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 1.99 Å3/Da / Density % sol: 38.34 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 50 mM KHPO4 pH 7.5, 1.7 M ammonium sulfate and 4% (v/v) PEG400, 5 mM ADP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→68.64 Å / Num. obs: 51337 / % possible obs: 98.1 % / Redundancy: 3 % / Biso Wilson estimate: 28.9 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.039 / Rrim(I) all: 0.069 / Net I/σ(I): 9.7
Reflection shellResolution: 1.95→2 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.354 / Mean I/σ(I) obs: 2 / Num. unique obs: 3739 / CC1/2: 0.815 / Rpim(I) all: 0.251 / Rrim(I) all: 0.436 / % possible all: 97.1

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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: 2zkj

2zkj


Resolution: 1.95→68.64 Å / SU ML: 0.2076 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.1605
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2286 2388 4.66 %
Rwork0.2021 48901 -
obs0.2034 51289 97.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.21 Å2
Refinement stepCycle: LAST / Resolution: 1.95→68.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5487 0 57 174 5718
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00225761
X-RAY DIFFRACTIONf_angle_d0.5137837
X-RAY DIFFRACTIONf_chiral_restr0.0397876
X-RAY DIFFRACTIONf_plane_restr0.0029999
X-RAY DIFFRACTIONf_dihedral_angle_d11.13142119
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.990.28941360.24262858X-RAY DIFFRACTION97.11
1.99-2.030.26521400.23692821X-RAY DIFFRACTION96.99
2.03-2.080.30321340.22482837X-RAY DIFFRACTION97.28
2.08-2.130.26981420.22062858X-RAY DIFFRACTION97.31
2.13-2.190.26811450.22022866X-RAY DIFFRACTION97.38
2.19-2.250.25621290.20732893X-RAY DIFFRACTION97.99
2.25-2.330.2591280.21462858X-RAY DIFFRACTION97.71
2.33-2.410.22651510.20922842X-RAY DIFFRACTION97.4
2.41-2.510.23921340.20972851X-RAY DIFFRACTION97.39
2.51-2.620.27081360.22252877X-RAY DIFFRACTION97.38
2.62-2.760.22871350.20872848X-RAY DIFFRACTION97.52
2.76-2.930.2411350.21152908X-RAY DIFFRACTION98.03
2.93-3.160.26311400.21392906X-RAY DIFFRACTION98.45
3.16-3.480.21361360.20272915X-RAY DIFFRACTION99.03
3.48-3.980.21671670.17892881X-RAY DIFFRACTION98.1
3.98-5.010.17371490.17542927X-RAY DIFFRACTION98.31
5.01-68.640.22821510.20342955X-RAY DIFFRACTION97.43
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.590232802260.125112672073-0.339023587121.80854206287-0.6396153049034.35403758167-0.02291292727430.0986565861665-0.208160905017-0.0834186703152-0.1059163474240.2078978798790.338510427795-0.2314669335530.09569534470230.204970403472-0.01082592609290.004387889677010.248685977459-0.04935903969070.241343287011-26.5761925448-11.2211267085.87355440116
22.495646618520.4093704612850.6959606308981.15582700880.5261229746172.15233770828-0.173968131673-0.1735878528060.325395746468-0.0655634173397-0.07332137668450.168451735465-0.126134921102-0.2226781542990.1013712099370.1684712986370.0546203596299-0.03427362687720.276830732612-0.01436791187090.255850257751-15.5468027489.1093612542813.7362848727
33.0372992557-1.48251485774-0.4522829280485.256747293033.205491454213.67803581276-0.0161767899186-0.0134004810291-0.4548081855820.691827563903-0.1534627826280.1621999979270.680022131812-0.1263637203240.1472621016860.236488399317-0.04372690498760.01762806570040.2166922268870.1103817134390.2692849727716.743851266-12.111380067336.7654037452
43.30676147767-0.0246549759984-0.3816773919373.449791702870.9031629105174.89182152882-0.1131417013790.141737385544-0.246028121624-0.07202625135640.0750661448042-0.1177154290620.02500210874580.06023629603920.04037050657120.1722466242310.02006344055320.02268283518080.1371477972410.002994773444580.30387661032425.3318398717-10.081087106428.431482261
51.88159114028-1.026117552640.1250701465163.119495519820.6969661484283.42774653538-0.00122469373927-0.0183998718761-0.008661903433230.04989866495320.0220315513197-0.115273196982-0.00906806647880.146005277471-0.04536871144120.134551058252-0.02057185608990.02949099850830.1705897414620.01471243651220.20549887119818.44608387070.67788186542932.4845484047
62.012635840770.4219744343150.4103114524821.37427718366-0.9712078948914.39930927346-0.01384727020010.1038550657210.220784622251-0.00806222667206-0.03990903588750.0186871860054-0.2210038994650.1409679424410.05960631470410.1520693436310.0129303383908-0.01129449187460.177392996853-0.0246448483010.2143232368837.9408171004116.987394170721.604081548
72.06131218675-0.9009653933710.7211174132012.90243388781-1.672728551930.9963068176490.1306276667150.266604352504-0.141658287542-0.382668474868-0.1506569948650.05488260397680.176492100660.002707972844320.04261475594780.210053377434-0.00359549311054-0.0186959493460.267403260325-0.043637201450.2357239324298.143893542791.5876050480420.7000654342
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 20 through 180 )AA20 - 1801 - 156
22chain 'A' and (resid 181 through 397 )AA181 - 397157 - 337
33chain 'B' and (resid 20 through 50 )BE20 - 501 - 27
44chain 'B' and (resid 51 through 152 )BE51 - 15228 - 122
55chain 'B' and (resid 153 through 199 )BE153 - 199123 - 169
66chain 'B' and (resid 200 through 307 )BE200 - 307170 - 277
77chain 'B' and (resid 308 through 386 )BE308 - 386278 - 349

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