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- PDB-8egd: Branched chain ketoacid dehydrogenase kinase in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 8egd
TitleBranched chain ketoacid dehydrogenase kinase in complex with inhibitor
Components[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial
KeywordsSIGNALING PROTEIN / Branched-chain ketoacid dehydrogenase / Branched-chain ketoacid dehydrogenase kinase / inhibitors / angiotensin receptor blocker / complex
Function / homology
Function and homology information


[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase / [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity / Branched-chain amino acid catabolism / : / valine catabolic process / isoleucine catabolic process / pyruvate dehydrogenase (acetyl-transferring) kinase activity / L-leucine catabolic process / branched-chain amino acid catabolic process / lipid biosynthetic process ...[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase / [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity / Branched-chain amino acid catabolism / : / valine catabolic process / isoleucine catabolic process / pyruvate dehydrogenase (acetyl-transferring) kinase activity / L-leucine catabolic process / branched-chain amino acid catabolic process / lipid biosynthetic process / protein serine/threonine phosphatase activity / regulation of glucose metabolic process / spermatogenesis / non-specific serine/threonine protein kinase / protein kinase activity / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / 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 / Signal transduction histidine kinase-related protein, C-terminal / 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
ADENOSINE-5'-DIPHOSPHATE / : / 5-(4-methoxyphenyl)-1H-tetrazole / Branched-chain alpha-ketoacid dehydrogenase kinase
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.047 Å
AuthorsLiu, S.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Biol.Chem. / Year: 2023
Title: Structural studies identify angiotensin II receptor blocker-like compounds as branched-chain ketoacid dehydrogenase kinase inhibitors.
Authors: Liu, S. / Kormos, B.L. / Knafels, J.D. / Sahasrabudhe, P.V. / Rosado, A. / Sommese, R.F. / Reyes, A.R. / Ward, J. / Roth Flach, R.J. / Wang, X. / Buzon, L.M. / Reese, M.R. / Bhattacharya, S. ...Authors: Liu, S. / Kormos, B.L. / Knafels, J.D. / Sahasrabudhe, P.V. / Rosado, A. / Sommese, R.F. / Reyes, A.R. / Ward, J. / Roth Flach, R.J. / Wang, X. / Buzon, L.M. / Reese, M.R. / Bhattacharya, S.K. / Omoto, K. / Filipski, K.J.
History
DepositionSep 12, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,56910
Polymers44,2621
Non-polymers1,3079
Water86548
1
A: [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial
hetero molecules

A: [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,13820
Polymers88,5232
Non-polymers2,61518
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_765-x+2,-y+1,z1
Buried area5400 Å2
ΔGint-114 kcal/mol
Surface area29780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.960, 111.960, 137.180
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number181
Space group name H-MP6422
Components on special symmetry positions
IDModelComponents
11A-545-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial / Branched-chain alpha-ketoacid dehydrogenase kinase / BCKD-kinase / BCKDHKIN


Mass: 44261.582 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Bckdk / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q00972, [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase

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Non-polymers , 6 types, 57 molecules

#2: 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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-WIH / 5-(4-methoxyphenyl)-1H-tetrazole


Mass: 176.175 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H8N4O / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 48 / 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: 2.8 Å3/Da / Density % sol: 56.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 100 mM sodium citrate pH 5.6, 800 mM lithium sulfate, and 750 mM ammonium sulfate
Temp details: 20C

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.047→96.96 Å / Num. obs: 24822 / % possible obs: 85.2 % / Redundancy: 19.1 % / Biso Wilson estimate: 52.15 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.015 / Net I/σ(I): 26.9
Reflection shellResolution: 2.047→2.19 Å / Redundancy: 21.2 % / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1241 / CC1/2: 0.863 / Rpim(I) all: 0.459 / % possible all: 52.1

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Processing

Software
NameVersionClassification
XDSdata reduction
BUSTER2.11.8 (24-FEB-2021)refinement
PDB_EXTRACT3.27data extraction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Starting model: 40 / Resolution: 2.047→96.96 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.927 / SU R Cruickshank DPI: 0.24 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.24 / SU Rfree Blow DPI: 0.197 / SU Rfree Cruickshank DPI: 0.198
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 4 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ...Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 4 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY NOTE 2 : PFE E 4000, represented by force field, Program OpenEye Scientific Software, Inc. helper Version: 2.4.1.2 (20170215), Method MMFF94s, weight 16.0 NOTE 3 : PFE E 4001, represented by force field, Program OpenEye Scientific Software, Inc. helper Version: 2.4.1.2 (20170215), Method MMFF94s, weight 16.0 NOTE 4 : PFE E 4002, represented by force field, Program OpenEye Scientific Software, Inc. helper Version: 2.4.1.2 (20170215), Method MMFF94s, weight 16.0
RfactorNum. reflection% reflectionSelection details
Rfree0.2653 1226 4.94 %RANDOM
Rwork0.2392 ---
obs0.2405 24822 76.1 %-
Displacement parametersBiso max: 137.07 Å2 / Biso mean: 64.02 Å2 / Biso min: 33.09 Å2
Baniso -1Baniso -2Baniso -3
1-1.3427 Å20 Å20 Å2
2--1.3427 Å20 Å2
3----2.6854 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.047→96.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2617 0 83 48 2748
Biso mean--69 51.78 -
Num. residues----325
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d978SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes526HARMONIC5
X-RAY DIFFRACTIONt_it2765HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion353SEMIHARMONIC5
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_contact2078SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2787HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3787HARMONIC20.87
X-RAY DIFFRACTIONt_omega_torsion2.77
X-RAY DIFFRACTIONt_other_torsion17.72
LS refinement shellResolution: 2.05→2.15 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3696 26 5.23 %
Rwork0.3183 471 -
all0.3209 497 -
obs--11.98 %
Refinement TLS params.Method: refined / Origin x: 101.864 Å / Origin y: 36.0704 Å / Origin z: 22.1676 Å
111213212223313233
T-0.4777 Å20.0745 Å2-0.0066 Å2--0.2701 Å2-0.0807 Å2---0.4765 Å2
L1.0572 °2-0.6564 °20.8326 °2-1.173 °2-1.1037 °2--4.7196 °2
S0.2504 Å °0.0803 Å °0.1196 Å °-0.1485 Å °-0.1648 Å °-0.0756 Å °0.474 Å °0.9393 Å °-0.0856 Å °
Refinement TLS groupSelection details: { A|* }

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