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Entry
Database: PDB / ID: 5m4h
TitleApplication of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
ComponentsHeat shock protein HSP 90-alpha
KeywordsSIGNALING PROTEIN / Off-Rate Screening / PDHK / HSP90 / SPR / kinase inhibitors / fragment screening / cancer / PDK1 / PDK2 / PDK3 / PDK4
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / sperm plasma membrane / chaperone-mediated autophagy / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / mitochondrial transport / Uptake and function of diphtheria toxin / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / protein import into mitochondrial matrix / dendritic growth cone / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / regulation of protein-containing complex assembly / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / axonal growth cone / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / nitric oxide metabolic process / eNOS activation / positive regulation of defense response to virus by host / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / response to salt stress / positive regulation of telomere maintenance via telomerase / Signaling by ERBB2 / cardiac muscle cell apoptotic process / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / activation of innate immune response / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / positive regulation of interferon-beta production / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein tyrosine kinase binding / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / nitric-oxide synthase regulator activity / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / brush border membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / response to estrogen / tau protein binding / Downregulation of ERBB2 signaling / histone deacetylase binding / neuron migration / Chaperone Mediated Autophagy / Aggrephagy / positive regulation of protein catabolic process / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding / MHC class II protein complex binding
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Histidine kinase-like ATPase, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Histidine kinase-like ATPase, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-7FX / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsBaker, L.M. / Brough, P. / Surgenor, A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.
Authors: Brough, P.A. / Baker, L. / Bedford, S. / Brown, K. / Chavda, S. / Chell, V. / D'Alessandro, J. / Davies, N.G. / Davis, B. / Le Strat, L. / Macias, A.T. / Maddox, D. / Mahon, P.C. / Massey, A. ...Authors: Brough, P.A. / Baker, L. / Bedford, S. / Brown, K. / Chavda, S. / Chell, V. / D'Alessandro, J. / Davies, N.G. / Davis, B. / Le Strat, L. / Macias, A.T. / Maddox, D. / Mahon, P.C. / Massey, A.J. / Matassova, N. / McKenna, S. / Meissner, J.W. / Moore, J.D. / Murray, J.B. / Northfield, C.J. / Parry, C. / Parsons, R. / Roughley, S.D. / Shaw, T. / Simmonite, H. / Stokes, S. / Surgenor, A. / Stefaniak, E. / Robertson, A. / Wang, Y. / Webb, P. / Whitehead, N. / Wood, M.
History
DepositionOct 18, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Mar 7, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.source
Revision 2.0Nov 6, 2019Group: Atomic model / Data collection / Category: atom_site / diffrn_detector / Item: _atom_site.occupancy / _diffrn_detector.detector
Revision 2.1Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,9473
Polymers28,5241
Non-polymers4232
Water4,882271
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-13 kcal/mol
Surface area9540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.011, 86.552, 96.957
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-619-

HOH

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Components

#1: Protein Heat shock protein HSP 90-alpha / Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / ...Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


Mass: 28523.869 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Tissue: Melanoma / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Organ: Skin / Plasmid: PET19 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-7FX / [2,4-bis(oxidanyl)phenyl]-[(7~{S})-7-(trifluoromethyl)-6,7-dihydro-5~{H}-pyrazolo[1,5-a]pyrimidin-4-yl]methanone


Mass: 327.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12F3N3O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 271 / 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: 2.35 Å3/Da / Density % sol: 47.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M Na Cacodylate pH 6.5 25% PEG 2K MME 0.2M MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SEALED TUBE / Type: BRUKER D8 QUEST / Wavelength: 1.51484 Å
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: Sep 9, 2016
RadiationMonochromator: CU Filter / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.51484 Å / Relative weight: 1
ReflectionResolution: 2→64.57 Å / Num. obs: 17134 / % possible obs: 92.3 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.1378 / Net I/σ(I): 7.84
Reflection shellResolution: 2→2.03 Å / Redundancy: 2.55 % / Rmerge(I) obs: 0.5165 / Mean I/σ(I) obs: 2.5 / % possible all: 94.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
SAINTdata reduction
SADABSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1uyl

1uyl


Resolution: 2→64.57 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.857 / SU B: 7.026 / SU ML: 0.18 / Cross valid method: THROUGHOUT / ESU R: 0.221 / ESU R Free: 0.227 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31703 815 4.8 %RANDOM
Rwork0.22381 ---
obs0.2282 16318 92.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 27.303 Å2
Baniso -1Baniso -2Baniso -3
1--1.02 Å2-0 Å2-0 Å2
2--0.71 Å2-0 Å2
3---0.3 Å2
Refinement stepCycle: 1 / Resolution: 2→64.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1617 0 28 271 1916
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.021681
X-RAY DIFFRACTIONr_bond_other_d0.0030.021602
X-RAY DIFFRACTIONr_angle_refined_deg1.9191.9842276
X-RAY DIFFRACTIONr_angle_other_deg1.0363.0023690
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7145209
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.77124.72272
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.36415300
X-RAY DIFFRACTIONr_dihedral_angle_4_deg26.24158
X-RAY DIFFRACTIONr_chiral_restr0.10.2260
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021882
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02369
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_it2.2882.571833
X-RAY DIFFRACTIONr_mcbond_other2.2742.569832
X-RAY DIFFRACTIONr_mcangle_it3.4253.8511040
X-RAY DIFFRACTIONr_mcangle_other3.4253.8521041
X-RAY DIFFRACTIONr_scbond_it2.8282.812848
X-RAY DIFFRACTIONr_scbond_other2.8042.793843
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.4074.091230
X-RAY DIFFRACTIONr_long_range_B_refined6.99824.478173
X-RAY DIFFRACTIONr_long_range_B_other6.77324.1037851
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.542 66 -
Rwork0.415 1182 -
obs--94.05 %

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