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

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Basic information

Entry
Database: PDB / ID: 7ebb
TitleCrystal structure of human pyruvate dehydrogenase kinase 4 in complex with compound 2
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
1H-pyrrolo[2,3-b]pyridine-3-carbonitrile / ADENOSINE-5'-DIPHOSPHATE / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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)92,27310
Polymers91,1982
Non-polymers1,0758
Water5,296294
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 area4790 Å2
ΔGint-103 kcal/mol
Surface area29980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.624, 69.360, 81.283
Angle α, β, γ (deg.)90.000, 100.117, 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, 302 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-42A / 1H-pyrrolo[2,3-b]pyridine-3-carbonitrile


Mass: 143.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H5N3 / 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 / Adenosine 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 / Water


Mass: 18.015 Da / Num. of mol.: 294 / 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: 2.15 Å3/Da / Density % sol: 42.76 %
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: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Sep 26, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→80.02 Å / Num. obs: 60356 / % possible obs: 99 % / Redundancy: 3.9 % / Biso Wilson estimate: 28.88 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.052 / Rpim(I) all: 0.03 / Rrim(I) all: 0.06 / Net I/σ(I): 13.9
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.391 / Mean I/σ(I) obs: 3.4 / Num. unique obs: 4397 / CC1/2: 0.9 / Rpim(I) all: 0.228 / Rrim(I) all: 0.453 / % possible all: 98.2

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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: 1.9→80.02 Å / SU ML: 0.1877 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.7452
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.219 2964 4.91 %
Rwork0.1947 57362 -
obs0.1959 60326 98.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.1 Å2
Refinement stepCycle: LAST / Resolution: 1.9→80.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5599 0 64 294 5957
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00235912
X-RAY DIFFRACTIONf_angle_d0.55838044
X-RAY DIFFRACTIONf_chiral_restr0.0426894
X-RAY DIFFRACTIONf_plane_restr0.00311030
X-RAY DIFFRACTIONf_dihedral_angle_d12.23572191
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.2471480.22682682X-RAY DIFFRACTION98.37
1.93-1.960.25281420.2222686X-RAY DIFFRACTION97.35
1.96-20.26151370.22142706X-RAY DIFFRACTION98.68
2-2.040.26571280.2122716X-RAY DIFFRACTION98.24
2.04-2.080.23571380.20482689X-RAY DIFFRACTION97.72
2.08-2.130.24731720.19752667X-RAY DIFFRACTION98.85
2.13-2.170.24151380.19582725X-RAY DIFFRACTION98.66
2.18-2.230.21851210.19892733X-RAY DIFFRACTION98.28
2.23-2.290.23461540.18852682X-RAY DIFFRACTION98.37
2.29-2.360.20751560.1932732X-RAY DIFFRACTION98.63
2.36-2.430.22761310.1862713X-RAY DIFFRACTION98.89
2.43-2.520.25711370.19762729X-RAY DIFFRACTION99
2.52-2.620.25611310.21152768X-RAY DIFFRACTION99.01
2.62-2.740.24681470.20412714X-RAY DIFFRACTION99.31
2.74-2.880.24981310.19422776X-RAY DIFFRACTION99.45
2.88-3.070.2281630.21742724X-RAY DIFFRACTION99.31
3.07-3.30.23161380.21192761X-RAY DIFFRACTION99.49
3.3-3.630.20991360.19022765X-RAY DIFFRACTION99.52
3.63-4.160.1991350.17432782X-RAY DIFFRACTION99.62
4.16-5.240.16641360.16522800X-RAY DIFFRACTION99.8
5.24-80.020.20971450.20872812X-RAY DIFFRACTION98.04
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)
13.816813639680.5311529364740.1422231396731.885981848092.021532114184.05258261854-0.1957953016840.279286779192-0.355705517944-0.341087289508-0.1180600495850.2210960448380.3823479873-0.09924888968970.2716079402580.2788203891040.03549051637780.05769067860680.242608400882-0.07906164652540.2589587172-22.67876815-12.8145716382-0.587834439268
22.36072684276-0.09123783886410.09746173202162.03882135248-0.7096821479614.92752622108-0.08494926465710.00355695834631-0.3753468246140.0310048370281-0.0367161389380.2793619642330.17506259809-0.3959751603170.085432031320.184525610045-0.001187630768130.06302229441640.196175535923-0.05110787160270.300469384275-28.5533187837-11.179367915710.7816500077
31.77521230150.4113104663760.9737970717112.017333639030.619555371963.36384715386-0.0771937723295-0.1586766382450.240739097902-0.148395614999-0.07435017504830.301699631929-0.648243141979-0.5870984311090.2474732950060.2800900160.124057056475-0.09426825299480.354839953366-0.00357495924550.331947489138-25.445599001615.310894281611.6553951844
44.406816413151.09690081660.2335816295793.03477797923-0.553834370281.19632774015-0.04341600262340.3027346087550.535275574113-0.6169190220190.1345651156090.051546097172-0.570975989186-0.231001240052-0.139349579820.3839480977530.0445506652917-0.05865827159690.2025302752870.09210235293250.299820694801-14.828497680820.03767434897.81168972487
52.539301545972.319229391312.74327209577.653914092876.604092834486.11327716356-0.252796485198-0.3826647371670.1372453113220.274650997222-0.2653465691680.5712619935520.298047507077-0.5825562016030.5395790300440.1512603553150.0683280580111-0.009826772910470.288320335499-0.009953544504410.266819690484-20.896931497211.662893045119.3787682274
62.834368084381.006706940060.8580127747913.9539801483-0.6938945875622.19638561788-0.0852902882784-0.2351875959520.2969518326970.1953598597720.009037236077420.0759507590897-0.367900710821-0.1092577365030.02253649633590.1722800261480.0567961804793-0.04167743250690.211128757161-0.02668824969520.192317144026-11.938393141617.893847239319.9791228491
72.705223418451.593493855763.516663553522.074394194312.108054116434.577589501280.302185196853-0.452389277022-0.08144231624860.271628203724-0.1570307044340.1192940501280.18960142272-0.810660303597-0.16465654820.248969735498-0.01552136600950.0259644748920.2964890854050.0471276827750.227939191859-15.37458784940.49857385076320.0939731994
82.55323076792.163410447083.615437115633.105055466864.600426284078.304151788890.045957113355-0.06145244090990.01940018047590.070348296891-0.0173090132882-0.09637612243920.1381039816770.00856282472251-0.07631346731110.2236629113680.0243266707485-0.01338665018880.1944402013220.01330733605960.210252570332-8.644411887599.4932684148717.8486859638
92.55643387531.094995330841.448744021160.7967591758361.054182601571.6654777463-0.00872530824754-0.178771512699-0.5445342397310.1369671288240.183464502968-0.13940066830.2607762759770.111821077564-0.1409141382610.3096458764810.08910844710750.08421788602920.376187969535-0.008522146577030.347962299295-8.43646249826-10.650740341710.9840391288
102.36080069693-0.1190409313890.7323090020892.231468479920.7342712021432.336066307790.008111757751940.0970505189505-0.314614690016-0.05311559529070.0196293437802-0.1711843991710.1009203263410.104614646222-0.0148247815790.19201751928-0.007585807457110.06200380895140.136593918180.01079669837890.31703862975122.3880956642-8.3774430223430.3929446104
111.80554677892-0.1656691664170.5789232483641.502269834-0.5633250194121.39792207633-0.1077807132640.1083305813310.130401829238-0.1424996647990.0262382243214-0.0820903625009-0.0719872273594-0.004304241316480.0875295131940.170758201699-0.02855157680240.01840457112540.163398809366-0.009637207504390.1779895979239.3694677801511.27017447623.2237114566
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 22 through 74 )AA22 - 741 - 49
22chain 'A' and (resid 75 through 180 )AA75 - 18050 - 155
33chain 'A' and (resid 181 through 219 )AA181 - 219156 - 187
44chain 'A' and (resid 220 through 244 )AA220 - 244188 - 212
55chain 'A' and (resid 245 through 266 )AA245 - 266213 - 234
66chain 'A' and (resid 267 through 299 )AA267 - 299235 - 267
77chain 'A' and (resid 300 through 344 )AA300 - 344268 - 292
88chain 'A' and (resid 345 through 365 )AA345 - 365293 - 313
99chain 'A' and (resid 366 through 396 )AA366 - 396314 - 338
1010chain 'B' and (resid 20 through 180 )BE20 - 1801 - 161
1111chain 'B' and (resid 181 through 386 )BE181 - 386162 - 359

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