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- PDB-4v25: VER-246608, a novel pan-isoform ATP competitive inhibitor of pyru... -

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Basic information

Entry
Database: PDB / ID: 4v25
TitleVER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context- dependent cytostasis in cancer cells
Components[PYRUVATE DEHYDROGENASE (ACETYL-TRANSFERRING)] KINASE ISOZYME 2, MITOCHONDRIAL
KeywordsTRANSFERASE / GLYCOLYSIS / WARBURG METABOLISM / NOV3R
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 / : / 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 ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / : / 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
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-SZ6 / Chem-TF3 / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsMoore, J.D. / Staniszewska, A. / Shaw, T. / D'Alessandro, J. / Davis, B. / Surgenor, A. / Baker, L. / Matassova, N. / Murray, J. / Macias, A. ...Moore, J.D. / Staniszewska, A. / Shaw, T. / D'Alessandro, J. / Davis, B. / Surgenor, A. / Baker, L. / Matassova, N. / Murray, J. / Macias, A. / Brough, P. / Wood, M. / Mahon, P.C.
CitationJournal: Oncotarget / Year: 2014
Title: VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells.
Authors: Moore, J.D. / Staniszewska, A. / Shaw, T. / D'Alessandro, J. / Davis, B. / Surgenor, A. / Baker, L. / Matassova, N. / Murray, J. / Macias, A. / Brough, P. / Wood, M. / Mahon, P.C.
History
DepositionOct 6, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 3, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2015Group: Database references
Revision 1.2Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Oct 9, 2019Group: Data collection / Database references / Other / Category: citation / pdbx_database_status
Item: _citation.page_last / _citation.pdbx_database_id_DOI ..._citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _pdbx_database_status.status_code_sf
Revision 1.4May 1, 2024Group: 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)47,2294
Polymers46,2911
Non-polymers9383
Water1,15364
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)94,4588
Polymers92,5812
Non-polymers1,8766
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_545-x,-y-1,z1
Buried area2650 Å2
ΔGint-25.9 kcal/mol
Surface area31830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.944, 108.944, 84.380
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 / PDKI I


Mass: 46290.727 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-SZ6 / N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-(4-{[(difluoroacetyl)amino]methyl}benzyl)-2,4-dihydroxybenzamide


Mass: 552.956 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H23ClF2N4O4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 64 / 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: 3.12 Å3/Da / Density % sol: 60.61 % / Description: NONE
Crystal growpH: 5.8
Details: 0.1 M SODIUM ACETATE PH 5.8, 0.125 M MAGNESIUM CHLORIDE AND 6% ISOPROPANOL, 4OC

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS4 / Detector: IMAGE PLATE / Date: Oct 23, 2012 / Details: OSMIC BLUE
RadiationMonochromator: CU FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. obs: 17281 / % possible obs: 98.3 % / Observed criterion σ(I): 1.5 / Redundancy: 2.31 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 5
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 2.19 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 1.3 / % possible all: 97.7

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: APO PDK2

Resolution: 2.6→25.01 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.93 / SU B: 12.022 / SU ML: 0.241 / Cross valid method: THROUGHOUT / ESU R: 0.405 / ESU R Free: 0.286 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25619 872 5 %RANDOM
Rwork0.19834 ---
obs0.20132 16403 98.08 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 63.207 Å2
Baniso -1Baniso -2Baniso -3
1-0.94 Å20.94 Å20 Å2
2--0.94 Å20 Å2
3----3.04 Å2
Refinement stepCycle: LAST / Resolution: 2.6→25.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2748 0 65 64 2877
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0192880
X-RAY DIFFRACTIONr_bond_other_d0.0020.022727
X-RAY DIFFRACTIONr_angle_refined_deg1.7381.9983897
X-RAY DIFFRACTIONr_angle_other_deg0.8853.0036239
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3085339
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.90224.016127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.99815492
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2271515
X-RAY DIFFRACTIONr_chiral_restr0.0870.2424
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213182
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02636
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.601→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.399 54 -
Rwork0.327 1194 -
obs--97.58 %

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