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- PDB-7vbv: Crystal structure of human pyruvate dehydrogenase kinase 2 in com... -

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Basic information

Entry
Database: PDB / ID: 7vbv
TitleCrystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 7
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
KeywordsTRANSFERASE/INHIBITOR / PDHK / KINASE INHIBITORS / FRAGMENT SCREENING / PDK1 / PDK2 / PDK3 / PDK4 / TRANSFERASE-INHIBITOR complex
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
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
Chem-67V / ACETATE ION / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsOrita, T. / Doi, S. / Iwanaga, T. / Fujishima, A. / Adachi, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors.
Authors: Bessho, Y. / Akaki, T. / Hara, Y. / Yamakawa, M. / Obika, S. / Mori, G. / Ubukata, M. / Yasue, K. / Nakane, Y. / Terasako, Y. / Orita, T. / Doi, S. / Iwanaga, T. / Fujishima, A. / Adachi, T. ...Authors: Bessho, Y. / Akaki, T. / Hara, Y. / Yamakawa, M. / Obika, S. / Mori, G. / Ubukata, M. / Yasue, K. / Nakane, Y. / Terasako, Y. / Orita, T. / Doi, S. / Iwanaga, T. / Fujishima, A. / Adachi, T. / Ueno, H. / Motomura, T.
History
DepositionSep 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)90,49914
Polymers89,2952
Non-polymers1,20412
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4790 Å2
ΔGint-24 kcal/mol
Surface area29640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.300, 109.300, 84.288
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31
Space group name HallP31
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 44647.730 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK2, PDHK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase

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Non-polymers , 5 types, 94 molecules

#2: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-67V / methyl 8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indole-3-carboxylate


Mass: 280.321 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H16N2O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 3.26 Å3/Da / Density % sol: 62.22 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 50 mM Na acetate pH 5.5, 100 mM magnesium chloride and 8% (v/v) isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.21→94.66 Å / Num. obs: 54702 / % possible obs: 97.3 % / Redundancy: 5.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.031 / Rrim(I) all: 0.073 / Net I/σ(I): 12.1
Reflection shellResolution: 2.21→2.27 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.653 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 4081 / CC1/2: 0.839 / Rpim(I) all: 0.311 / Rrim(I) all: 0.724 / % possible all: 97.7

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
DIALSdata reduction
Aimlessdata scaling
Cootmodel building
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7EBH

7ebh


Resolution: 2.21→62.95 Å / Cross valid method: FREE R-VALUE / σ(F): 55.14 / Phase error: 26.9241
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2389 2839 5.19 %
Rwork0.2022 51849 -
obs0.2125 54688 97.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 59.13 Å2
Refinement stepCycle: LAST / Resolution: 2.21→62.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5404 0 79 82 5565
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00395600
X-RAY DIFFRACTIONf_angle_d0.45797571
X-RAY DIFFRACTIONf_chiral_restr0.0387832
X-RAY DIFFRACTIONf_plane_restr0.0054966
X-RAY DIFFRACTIONf_dihedral_angle_d10.59452084
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.21-2.250.3173960.31612664X-RAY DIFFRACTION94.4
2.25-2.290.36621260.30912628X-RAY DIFFRACTION93.66
2.29-2.340.30451500.31112628X-RAY DIFFRACTION92.37
2.34-2.380.32281600.30542598X-RAY DIFFRACTION93.02
2.38-2.440.30821540.28762609X-RAY DIFFRACTION93.01
2.44-2.490.27831520.29542616X-RAY DIFFRACTION92.57
2.49-2.550.30071420.29052634X-RAY DIFFRACTION93.11
2.55-2.620.29561590.28162538X-RAY DIFFRACTION92.16
2.62-2.70.33561420.27352434X-RAY DIFFRACTION85.73
2.7-2.790.27081470.26992625X-RAY DIFFRACTION93.32
2.79-2.890.32421480.26712613X-RAY DIFFRACTION93.62
2.89-30.25451320.26282658X-RAY DIFFRACTION93.89
3-3.140.22651400.24142640X-RAY DIFFRACTION94.05
3.14-3.310.3141520.23442604X-RAY DIFFRACTION93.37
3.31-3.510.25111530.22592394X-RAY DIFFRACTION85.01
3.51-3.780.22561500.19492604X-RAY DIFFRACTION93.13
3.78-4.160.23141240.17142677X-RAY DIFFRACTION95.1
4.16-4.770.1751440.15482621X-RAY DIFFRACTION92.94
4.77-60.2171250.16332496X-RAY DIFFRACTION88.6
6.01-62.950.22871370.18192574X-RAY DIFFRACTION92.03
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)
11.36035934562-0.376992690438-0.188025645421.958053414350.3874150326091.83787473976-0.0956366043482-0.2912229080180.03442528281440.558777441243-0.0438008396508-0.50586340415-0.1000127231040.3521923693480.0007908679823370.7134322677570.0822384257004-0.2698066238620.5647633523320.0164856755970.4616750494754.369702717446.398621797484.1836771175
23.299656171960.9811643896550.270381115182.446787404950.5922505068941.60766954352-0.1840567723730.596900597855-0.1839856276840.111141344050.118586841003-0.296525687938-0.01567799878080.193026505791-0.009123223550620.3761176764520.0522635727362-0.02685818021820.477372969835-0.0301569997640.29246467427640.262156352745.131811395661.571977254
31.21493924959-0.713568301389-0.5316096574631.90440254599-0.1787402221012.35274607028-0.229219632896-0.18900932333-0.102190532740.5248160451050.05891560771680.490171045374-0.0302891382646-0.317090241782-0.0009742490875650.7705927161260.09931407497340.2633356627090.5046677126370.001464237698420.5093748393060.58446490651448.741243018484.5952537114
43.587610796290.63678345007-0.3920759139991.91792344582-0.3994089940271.65492380417-0.0622174436710.5173229300920.2386476733580.2268589644010.02091120179170.340919553396-0.0958394917052-0.159080797861-0.006426647835210.4201956749790.0556007642880.008770039092880.5475615407870.02875201861720.28858856252514.327290632950.159171090661.4467312012
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 14 through 175 )AA14 - 1751 - 162
22chain 'A' and ((resid 176 through 374 ) or (resid 5000))AA - G176 - 5000163
33chain 'B' and (resid 14 through 175 )BH14 - 1751 - 156
44chain 'B' and ((resid 176 through 372 ) or (resid 5000))BH - N176 - 5000157

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