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- PDB-2q8g: Structure of pyruvate dehydrogenase kinase isoform 1 in complex w... -

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Basic information

Entry
Database: PDB / ID: 2q8g
TitleStructure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545
Components[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1
KeywordsTRANSFERASE / GHKL ATPase/kinase family / pyruvate dehydrogenase complex / mitochondrial kinase / glucose-lowering drug AZD7545
Function / homology
Function and homology information


hypoxia-inducible factor-1alpha signaling pathway / [pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / : / Regulation of pyruvate dehydrogenase (PDH) complex / Signaling by Retinoic Acid / intrinsic apoptotic signaling pathway in response to oxidative stress / regulation of glucose metabolic process / glucose metabolic process ...hypoxia-inducible factor-1alpha signaling pathway / [pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / : / Regulation of pyruvate dehydrogenase (PDH) complex / Signaling by Retinoic Acid / intrinsic apoptotic signaling pathway in response to oxidative stress / regulation of glucose metabolic process / glucose metabolic process / cell population proliferation / mitochondrial matrix / protein kinase activity / phosphorylation / mitochondrion / ATP binding
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 / Histidine kinase/HSP90-like ATPase superfamily / Up-down Bundle / 2-Layer Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-AZX / : / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsKato, M. / Li, J. / Chuang, J.L. / Chuang, D.T.
CitationJournal: Structure / Year: 2007
Title: Distinct Structural Mechanisms for Inhibition of Pyruvate Dehydrogenase Kinase Isoforms by AZD7545, Dichloroacetate, and Radicicol.
Authors: Kato, M. / Li, J. / Chuang, J.L. / Chuang, D.T.
History
DepositionJun 10, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 24, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Revision 1.4Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8803
Polymers46,3621
Non-polymers5182
Water5,675315
1
A: [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1
hetero molecules

A: [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,7596
Polymers92,7232
Non-polymers1,0364
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area5890 Å2
ΔGint-36 kcal/mol
Surface area32380 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)96.979, 96.979, 111.352
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-633-

HOH

DetailsThe second part of the biological assembly is generated by the following operation: Y,X,-Z

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Components

#1: Protein [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1 / Pyruvate dehydrogenase kinase isoform 1


Mass: 46361.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK1 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: Q15118, [pyruvate dehydrogenase (acetyl-transferring)] kinase
#2: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#3: Chemical ChemComp-AZX / 4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE


Mass: 478.870 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18ClF3N2O5S
Details: AZD75445 was generously supplied by Dr. Rachel Mayers at AstraZeneca.
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 315 / Source method: isolated from a natural source / Formula: H2O

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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: 2.82 Å3/Da / Density % sol: 56.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: AZD75445 was generously supplied by Dr. Rachel Mayers at AstraZeneca, 0.42 M NaK tartrate, 0.1 M Na citrate, pH 5.6, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.98 Å
DetectorType: SBC-3 / Detector: CCD / Date: Oct 26, 2006 / Details: mirror
RadiationMonochromator: si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 42222 / % possible obs: 99.3 % / Redundancy: 9.1 % / Rmerge(I) obs: 0.063 / Χ2: 0.788 / Net I/σ(I): 6.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.9-1.978.70.43441510.8391100
1.97-2.059.30.62741810.7581100
2.05-2.149.40.31941790.777199.9
2.14-2.259.40.22941991.041100
2.25-2.399.40.19741910.918199.9
2.39-2.589.40.12642100.783199.9
2.58-2.849.30.07942420.72199.8
2.84-3.259.20.05442370.672199.4
3.25-4.098.90.0442400.818198.1
4.09-508.30.02743920.537196.4

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT2data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: pdb entry 2Q8F

2q8f


Resolution: 1.9→50 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.936 / SU B: 8.341 / SU ML: 0.122 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.152 / ESU R Free: 0.144 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.249 2058 5.1 %RANDOM
Rwork0.212 ---
obs0.214 40553 95.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.434 Å2
Baniso -1Baniso -2Baniso -3
1-0.69 Å20 Å20 Å2
2--0.69 Å20 Å2
3----1.38 Å2
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2978 0 32 315 3325
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0223096
X-RAY DIFFRACTIONr_angle_refined_deg1.6961.9764205
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1775366
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.54723.6150
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.95715519
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5521522
X-RAY DIFFRACTIONr_chiral_restr0.120.2453
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022382
X-RAY DIFFRACTIONr_nbd_refined0.2170.21460
X-RAY DIFFRACTIONr_nbtor_refined0.3120.22106
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.2262
X-RAY DIFFRACTIONr_metal_ion_refined0.2560.25
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1830.256
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2010.227
X-RAY DIFFRACTIONr_mcbond_it1.0981.51845
X-RAY DIFFRACTIONr_mcangle_it1.95622994
X-RAY DIFFRACTIONr_scbond_it3.16631276
X-RAY DIFFRACTIONr_scangle_it4.6264.51211
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.421 162 -
Rwork0.363 2879 -
obs-3041 98.73 %

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