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Basic information

Entry
Database: PDB / ID: 7eat
TitleCrystal structure of human pyruvate dehydrogenase kinase 4 in complex with compound 1
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 acetyl-CoA biosynthetic process from pyruvate / regulation of fatty acid oxidation / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of fatty acid biosynthetic process / regulation of cellular ketone metabolic process / regulation of pH / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of bone resorption / cellular response to fatty acid ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / regulation of fatty acid oxidation / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of fatty acid biosynthetic process / regulation of cellular ketone metabolic process / regulation of pH / Regulation of pyruvate dehydrogenase (PDH) complex / regulation of bone resorption / cellular response to fatty acid / Signaling by Retinoic Acid / response to starvation / negative regulation of anoikis / regulation of glucose metabolic process / reactive oxygen species metabolic process / cellular response to starvation / glucose homeostasis / insulin receptor signaling pathway / mitochondrial matrix / protein kinase activity / phosphorylation / mitochondrion / ATP binding
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
1,3-dihydro-2H-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: 2.1 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 8, 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 4, mitochondrial
B: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,8488
Polymers91,1982
Non-polymers6516
Water3,441191
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3630 Å2
ΔGint-67 kcal/mol
Surface area28650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.363, 67.979, 78.945
Angle α, β, γ (deg.)90.000, 101.110, 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

#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) / Strain (production host): BL21(DE3)
References: UniProt: Q16654, [pyruvate dehydrogenase (acetyl-transferring)] kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-W6P / 1,3-dihydro-2H-indol-2-one / Oxindole


Mass: 133.147 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H7NO / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.03 Å3/Da / Density % sol: 39.45 %
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: Photon Factory / Beamline: BL-17A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Oct 29, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→77.47 Å / Num. obs: 42561 / % possible obs: 99.4 % / Redundancy: 3.7 % / Biso Wilson estimate: 25.88 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.042 / Rrim(I) all: 0.081 / Net I/σ(I): 9.7
Reflection shellResolution: 2.1→3.8 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.258 / Mean I/σ(I) obs: 3.1 / Num. unique obs: 3104 / CC1/2: 0.926 / Rpim(I) all: 0.154 / Rrim(I) all: 0.301 / % possible all: 99.2

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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: 2.1→77.47 Å / SU ML: 0.2533 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.2418
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2283 2057 4.84 %
Rwork0.194 40474 -
obs0.1957 42531 99.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.64 Å2
Refinement stepCycle: LAST / Resolution: 2.1→77.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5406 0 40 191 5637
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025664
X-RAY DIFFRACTIONf_angle_d0.46787698
X-RAY DIFFRACTIONf_chiral_restr0.0394860
X-RAY DIFFRACTIONf_plane_restr0.0032988
X-RAY DIFFRACTIONf_dihedral_angle_d10.76042086
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.150.28731490.22072660X-RAY DIFFRACTION98.94
2.15-2.20.26181420.2192683X-RAY DIFFRACTION99.05
2.2-2.260.30161370.20972692X-RAY DIFFRACTION99.61
2.26-2.330.22211380.20542675X-RAY DIFFRACTION99.47
2.33-2.40.27291270.19842680X-RAY DIFFRACTION99.22
2.4-2.490.22881320.19972706X-RAY DIFFRACTION99.37
2.49-2.590.26831290.20992701X-RAY DIFFRACTION99.47
2.59-2.710.27731540.20992696X-RAY DIFFRACTION99.41
2.71-2.850.24531220.20322698X-RAY DIFFRACTION99.61
2.85-3.030.23161230.20942707X-RAY DIFFRACTION99.65
3.03-3.260.24661470.20322721X-RAY DIFFRACTION99.41
3.26-3.590.25491310.18732714X-RAY DIFFRACTION99.65
3.59-4.110.16791410.16782702X-RAY DIFFRACTION99.37
4.11-5.180.18441260.1642724X-RAY DIFFRACTION98.72
5.18-77.470.21311590.20882715X-RAY DIFFRACTION97.19
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)
11.713633759790.17351748212-0.08188965849841.5798499709-0.7542691214343.797048793710.01508367386320.0692773398516-0.188448416782-0.047031188992-0.07447854536210.1304682647740.254710947898-0.1213411720090.03893317286550.2080836837380.002215621758990.006235782887950.231250359274-0.05285909686650.278759879566-26.7334296071-11.42439169935.91312887
21.917237893630.3870516121790.7822411084291.27715139420.5803780997491.6499116236-0.145731123403-0.09197215850440.262003938783-0.10871975202-0.0684466078360.152951598932-0.146156228317-0.1592229505260.06707922397290.1802753930860.0354867015356-0.02812475946730.276190639842-0.003750371734060.286418356212-16.31342969769.3539158865513.383438311
33.54064866995-2.6283843313-2.136378746926.613949733843.51354019653.10002369703-0.261657569182-0.165944247346-0.3980090917020.6673728669210.1186004783790.3920301315430.5302002328310.09850730078420.1631374998650.315839980103-0.0143857874105-0.007260964709850.2776585396770.1054875077810.32744740648616.5935545679-12.288370165936.6413606618
42.98518138596-0.439305523901-0.3187971146822.421525556960.3142355648884.18088584163-0.08169117780450.144148505986-0.4521065843490.01243364368450.1055561222360.02046558522820.3769799354660.102814543778-0.02365150457480.2192285445830.003334508509870.02887679279360.1616052567720.007502397306350.3786000488824.182064794-13.006181195627.8040048482
53.75402453005-0.5486450837311.383263645543.42935100260.2246825611276.42011496728-0.1499214148490.1116284056240.02167415869490.04490568497130.0544252641602-0.342579414029-0.5304996539140.413467422340.08435547561250.1714779632880.009014599936810.02566092100290.180487325707-0.002341153823380.28481456373927.7883377552-6.2222421899329.5124318935
61.83947060218-1.26081572061-0.1259056530353.035283305120.793403027533.26942889941-0.0756099896803-0.0238524393494-0.008724330863410.0209829745182-0.00704814164483-0.0582326528749-0.0630811055350.1481884293140.06724794042980.141591097651-0.01225062090240.03102129612450.1850846601590.009584262272210.21934647742318.50111224610.6570373872332.3025787284
74.317357632961.55855017591-3.896619255272.59284138116-2.916151793377.653041171720.123549573758-0.1101548865630.4389704377060.169874732574-0.147325281173-0.20231388116-0.8236260518380.8898181223820.05800041734210.256279819867-0.0636241777898-0.03670985600150.3407092958320.009694548145180.31099760409616.102109472821.004369022821.5510941786
82.459059764640.213162110311-0.8625433275142.100918532960.07698509098882.73528895327-0.0481255466566-0.07034439118250.2840488055070.2309101541270.04039517219230.311407430575-0.414235661012-0.134903233824-0.007737144315350.2511050423010.00254081164364-0.04011523319930.25659513026-0.09257009637840.2421772763824.4846568970419.437715582332.117444383
93.13593060623-0.9238769527433.567180775544.23703979442-5.291091525668.76049344275-0.07530262622890.4146124413150.232360307996-0.279739593214-0.236491410313-0.04597262590510.161974258760.3746702531070.3502125577080.166970866374-0.01295730474340.007127634709670.261145698009-0.01250781865650.21061977059912.33763185214.284975595919.3484131487
102.920467092020.237437225651-0.08044707736581.47514018432-0.2586057956443.827800846850.04549674740350.1253633279790.282082842855-0.06593016411710.15221686990.181110333769-0.34421663565-0.0104444358172-0.2116907049590.1400986010970.0171213989787-0.01407685639630.201907989715-0.002596458788910.2542402376462.2295449237717.437514656617.9097037924
110.9658475453550.766996310728-0.3810990244870.6286066278920.02248544848525.856593287090.2043860616360.270754832039-0.2980715156-0.550434816902-0.3057345409670.3742225094650.0775181752872-0.2857543795350.1439910849440.3478967307320.112919799866-0.05985813972950.239399581231-0.05541461304650.21779747638410.3290584032.5424077886517.6586389434
121.1766534011-1.518612596781.934449192753.66950746263-4.912359265228.505773092790.0118974081238-0.05016375029070.0663887463117-0.144417262350.2469970998030.2936684845470.123362219166-0.492688093905-0.3054997676960.121619905174-0.0154018393486-0.01421082937670.2309267928240.001298908500870.2260299697051.214126719289.0309832965120.8774316522
131.38653024161-0.398887150016-0.6142311385254.336382076871.780422577784.524425629780.2499155238030.468006194436-0.740002192871-0.439747810937-0.4026619696580.262505922692-0.0122655068979-0.6462017224080.157086021710.229504271847-0.0366371144646-0.04357783559260.376641403506-0.09718276869240.5284249093937.48124434057-9.8114884470427.877724031
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 - 154
22chain 'A' and (resid 181 through 396 )AA181 - 396155 - 337
33chain 'B' and (resid 20 through 49 )BF20 - 491 - 27
44chain 'B' and (resid 50 through 103 )BF50 - 10328 - 81
55chain 'B' and (resid 104 through 152 )BF104 - 15282 - 123
66chain 'B' and (resid 153 through 199 )BF153 - 199124 - 170
77chain 'B' and (resid 200 through 219 )BF200 - 219171 - 190
88chain 'B' and (resid 220 through 244 )BF220 - 244191 - 215
99chain 'B' and (resid 245 through 266 )BF245 - 266216 - 237
1010chain 'B' and (resid 267 through 302 )BF267 - 302238 - 273
1111chain 'B' and (resid 303 through 343 )BF303 - 343274 - 294
1212chain 'B' and (resid 344 through 365 )BF344 - 365295 - 316
1313chain 'B' and (resid 366 through 386 )BF366 - 386317 - 337

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