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- PDB-9m3t: Crystal structure of human pyruvate dehydrogenase kinase isoform ... -

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Basic information

Entry
Database: PDB / ID: 9m3t
TitleCrystal structure of human pyruvate dehydrogenase kinase isoform 2 in complex with ATP competitive inhibitor 22
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
KeywordsTRANSFERASE / ghkl atpase/kinase family / pyruvate dehydrogenase complex / mitochondrial kinase
Function / homology
Function and homology information


[pyruvate dehydrogenase (acetyl-transferring)] kinase / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of pyruvate decarboxylation to acetyl-CoA / Regulation of pyruvate dehydrogenase (PDH) complex / pyruvate dehydrogenase complex / regulation of ketone metabolic process / regulation of pH / cellular response to nutrient / Signaling by Retinoic Acid / regulation of gluconeogenesis ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / pyruvate dehydrogenase (acetyl-transferring) kinase activity / regulation of pyruvate decarboxylation to acetyl-CoA / Regulation of pyruvate dehydrogenase (PDH) complex / pyruvate dehydrogenase complex / regulation of ketone metabolic process / 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
: / Chem-TF3 / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 Å
AuthorsXu, Z.H. / Chen, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2025
Title: Discovery of ATP competitive PDHK1/2 dual inhibitors.
Authors: Xu, H. / Ding, D. / Han, X. / Miao, K. / Liang, C. / Yun, H. / Zhu, W. / Dey, F. / Zhao, D. / Wu, Y. / Reutlinger, M. / Yang, J. / Zhai, G. / Lin, Z. / Li, C. / Wu, W. / Xu, B. / Han, L. / ...Authors: Xu, H. / Ding, D. / Han, X. / Miao, K. / Liang, C. / Yun, H. / Zhu, W. / Dey, F. / Zhao, D. / Wu, Y. / Reutlinger, M. / Yang, J. / Zhai, G. / Lin, Z. / Li, C. / Wu, W. / Xu, B. / Han, L. / Chen, S. / Huang, X. / Casagrande, F. / Hilbert, M. / Strebel, Q. / Wichert, M. / Westwood, P. / Schafer, R. / Roth, D. / Heer, D. / Tian, X. / Ma, T. / Zhang, T. / Zhao, J. / Urich, E. / Xia, G. / Lassen, K. / Shen, H.C. / Zou, G.
History
DepositionMar 3, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release

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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 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7005
Polymers41,7221
Non-polymers9784
Water2,684149
1
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)85,39910
Polymers83,4432
Non-polymers1,9568
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_655-x+1,-y,z1
Buried area6850 Å2
ΔGint-13 kcal/mol
Surface area30740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.570, 106.570, 85.660
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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Components

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


Mass: 41721.609 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)
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase
#2: Chemical ChemComp-TF3 / N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL} ACETAMIDE


Mass: 360.878 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25ClN2O2
#3: Chemical ChemComp-A1EQI / 2-chloranyl-4-[[(3R)-1-[(3S)-7-(ethylamino)-5-fluoranyl-3-methyl-2-oxidanylidene-1H-indol-3-yl]piperidin-3-yl]amino]benzoic acid


Mass: 460.929 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26ClFN4O3 / Feature type: SUBJECT OF INVESTIGATION
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 149 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.48 Å3/Da / Density % sol: 64.66 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.42 M NaK tartrate, 0.1 M Na citrate, pH 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9793 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.08→46.15 Å / Num. obs: 33296 / % possible obs: 100 % / Redundancy: 20.6 % / CC1/2: 0.995 / Rmerge(I) obs: 0.161 / Rpim(I) all: 0.037 / Rrim(I) all: 0.165 / Χ2: 1.01 / Net I/σ(I): 12.1 / Num. measured all: 684879
Reflection shellResolution: 2.08→2.14 Å / % possible obs: 100 % / Redundancy: 20.9 % / Rmerge(I) obs: 1.448 / Num. measured all: 54750 / Num. unique obs: 2623 / CC1/2: 0.847 / Rpim(I) all: 0.324 / Rrim(I) all: 1.484 / Χ2: 0.93 / Net I/σ(I) obs: 2.4

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Processing

Software
NameVersionClassification
PHENIX(1.19rc4_4035: ???)refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.08→46.15 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2046 1579 4.74 %
Rwork0.1745 --
obs0.1759 33286 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.08→46.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2836 0 65 149 3050
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073052
X-RAY DIFFRACTIONf_angle_d0.8784142
X-RAY DIFFRACTIONf_dihedral_angle_d12.781184
X-RAY DIFFRACTIONf_chiral_restr0.054444
X-RAY DIFFRACTIONf_plane_restr0.007537
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.08-2.150.28431450.23572890X-RAY DIFFRACTION100
2.15-2.220.19931310.20132866X-RAY DIFFRACTION100
2.22-2.310.24251610.20942874X-RAY DIFFRACTION100
2.31-2.420.24431330.19532866X-RAY DIFFRACTION100
2.42-2.550.21491390.19322860X-RAY DIFFRACTION100
2.55-2.710.22091100.19732911X-RAY DIFFRACTION100
2.71-2.910.23481780.20212833X-RAY DIFFRACTION100
2.91-3.210.22851660.19872862X-RAY DIFFRACTION100
3.21-3.670.20851550.16772883X-RAY DIFFRACTION100
3.67-4.620.16571430.14592893X-RAY DIFFRACTION100
4.63-46.150.19321180.16492969X-RAY DIFFRACTION100
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)
13.3829-0.30540.68472.59190.492.22070.24360.8701-0.3957-0.4192-0.05510.24650.3634-0.4672-0.09930.51390.0433-0.17730.542-0.09950.553632.414-19.8899-42.9165
23.9741-0.887-0.37161.40870.03942.3040.33230.4662-0.7088-0.172-0.18190.10590.3626-0.1356-0.13050.49150.0454-0.10550.3708-0.11990.426744.5537-24.8512-41.2541
32.83960.8170.71464.03110.57562.69410.0519-0.3794-0.15020.6494-0.00240.11210.3426-0.2349-0.080.4847-0.02330.10180.33290.05770.326641.7531-16.3622-12.8828
43.05341.16580.10442.2150.38391.59630.0946-0.1272-0.28470.25990.0594-0.23860.23840.0576-0.13510.4760.0557-0.04150.30250.01480.323354.8056-10.8418-16.9216
52.57270.24580.97682.12480.69981.9280.15060.4174-0.2047-0.2814-0.0006-0.0880.10930.1586-0.09010.40210.05520.00630.30080.01070.299249.8534-10.1583-30.6678
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 16 through 70 )
2X-RAY DIFFRACTION2chain 'A' and (resid 71 through 175 )
3X-RAY DIFFRACTION3chain 'A' and (resid 176 through 241 )
4X-RAY DIFFRACTION4chain 'A' and (resid 242 through 304 )
5X-RAY DIFFRACTION5chain 'A' and (resid 305 through 382 )

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