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- PDB-8zm2: Structure of human pyruvate dehydrogenase kinase 2 complexed with... -

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Basic information

Entry
Database: PDB / ID: 8zm2
TitleStructure of human pyruvate dehydrogenase kinase 2 complexed with compound 16
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
KeywordsTRANSFERASE / pdhk / kinase inhibitors / fragment screening / pdk1 / pdk2 / pdk3 / pdk4 / transferase-inhibitor complex / transferase/inhibitor
Function / homology
Function and homology information


[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / : / pyruvate dehydrogenase complex / regulation of cellular ketone metabolic process / regulation of pH / cellular response to nutrient / Regulation of pyruvate dehydrogenase (PDH) complex / Signaling by Retinoic Acid ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / : / pyruvate dehydrogenase complex / regulation of cellular ketone metabolic process / regulation of pH / cellular response to nutrient / Regulation of pyruvate dehydrogenase (PDH) complex / 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 / phosphorylation / 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
: / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.34 Å
AuthorsAkai, S. / Orita, T. / Nomura, A. / Adachi, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2024
Title: Design and synthesis of novel fluorene derivatives as inhibitors of pyruvate dehydrogenase kinase.
Authors: Inoue, M. / Nagamori, H. / Morita, T. / Kobayashi, S. / Suzawa, K. / Kitao, Y. / Saito, T. / Kawahara, I. / Orita, T. / Akai, S. / Adachi, T. / Motomura, T.
History
DepositionMay 22, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)44,9562
Polymers44,6481
Non-polymers3081
Water1,18966
1
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules

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


  • defined by author&software
  • Evidence: gel filtration
  • 89.9 kDa, 2 polymers
Theoretical massNumber of molelcules
Total (without water)89,9124
Polymers89,2952
Non-polymers6172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_655-x+1,-y,z1
Buried area2330 Å2
ΔGint-17 kcal/mol
Surface area32300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.886, 108.886, 84.421
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Space group name HallP64
Symmetry operation#1: x,y,z
#2: x-y,x,z+2/3
#3: y,-x+y,z+1/3
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z

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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: 44647.730 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-A1L17 / methyl (9~{R})-9-oxidanyl-9-(trifluoromethyl)fluorene-4-carboxylate


Mass: 308.252 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H11F3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 3.24 Å3/Da / Density % sol: 61.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 50mM Na acetate pH 5.5, 100mM magnesium chloride, 8% (v/v) isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-5A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 13, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.33→94.3 Å / Num. obs: 24368 / % possible obs: 100 % / Redundancy: 11.2 % / Biso Wilson estimate: 47.97 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.021 / Rrim(I) all: 0.069 / Net I/σ(I): 23.4
Reflection shellResolution: 2.33→2.39 Å / Rmerge(I) obs: 0.985 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 1776 / CC1/2: 0.839 / Rpim(I) all: 0.305 / Rrim(I) all: 1.032

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.34→94.3 Å / SU ML: 0.2963 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.2086
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2195 1162 4.81 %
Rwork0.1992 23020 -
obs0.2002 24182 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 63.17 Å2
Refinement stepCycle: LAST / Resolution: 2.34→94.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2757 0 22 66 2845
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00182858
X-RAY DIFFRACTIONf_angle_d0.42213875
X-RAY DIFFRACTIONf_chiral_restr0.0384424
X-RAY DIFFRACTIONf_plane_restr0.0033495
X-RAY DIFFRACTIONf_dihedral_angle_d9.87371069
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.34-2.440.33421340.26812855X-RAY DIFFRACTION99.97
2.44-2.570.23581280.22942869X-RAY DIFFRACTION99.97
2.57-2.730.24671520.24632873X-RAY DIFFRACTION99.97
2.73-2.940.28561540.24272883X-RAY DIFFRACTION100
2.94-3.240.22661350.23932880X-RAY DIFFRACTION100
3.24-3.710.2281650.19772857X-RAY DIFFRACTION100
3.71-4.670.16671440.16962887X-RAY DIFFRACTION100
4.67-94.30.21751500.17662916X-RAY DIFFRACTION99.35
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)
10.38937388622-0.199370352381.149027676372.814147363340.0578819507723.551301189640.1464421845580.815157788677-0.411845188588-0.664835729694-0.2833317063370.2890565786580.284361186038-0.1543365974480.1609343056420.6074864403670.0617011276304-0.1518471278670.677025153164-0.2890539685130.67054799660438.4252377703-22.75371671314.2452335208
21.56195794597-1.07085473637-1.03015725641.18952864179-0.2264423809443.235070810970.1337679383430.163011208278-0.520904671176-0.453744733451-0.2721157566670.2194100764190.339386421707-0.080227984687-0.005488062229430.6624846162980.0818995380596-0.08409489227320.471498357519-0.1704806407330.63665466249245.1794314547-24.370606468320.0082873357
33.298354771051.275291618710.3353788448234.768371097850.2201427773283.255028783610.418266660171-0.704395797293-0.4641982772490.924361175984-0.560456196860.2215081367170.158826494597-0.3330756669070.1123644659390.65745534443-0.1952265271410.06794630244540.4773060886960.0500955562410.53612358068442.8611385465-16.656518103445.5952831877
43.714571359461.319893932680.6266679480513.053879215160.4399269048722.067552979310.4434381710570.0660399086831-0.5459901598350.15821296642-0.384673299835-0.2156731453570.2055811229460.120079327144-0.1025154166960.4447789975350.04736676168-0.05538797049880.3243623981240.007211116450860.36716260008552.929507831-10.245855594435.938274615
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 14 through 98 )14 - 981 - 85
22chain 'A' and (resid 99 through 175 )99 - 17586 - 162
33chain 'A' and (resid 176 through 241 )176 - 241163 - 222
44chain 'A' and (resid 242 through 376 )242 - 376223 - 343

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