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- PDB-2wi3: Orally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Ch... -

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Basic information

Entry
Database: PDB / ID: 2wi3
TitleOrally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Chaperone
ComponentsHEAT SHOCK PROTEIN, HSP 90-ALPHAHeat shock response
KeywordsCHAPERONE / HEAT SHOCK / STRESS RESPONSE / NUCLEOTIDE-BINDING
Function / homology
Function and homology information


Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Regulation of actin dynamics for phagocytic cup formation / Recruitment of NuMA to mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Loss of Nlp from mitotic centrosomes / HSF1-dependent transactivation / VEGFA-VEGFR2 Pathway / Attenuation phase / HSF1 activation ...Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Regulation of actin dynamics for phagocytic cup formation / Recruitment of NuMA to mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Loss of Nlp from mitotic centrosomes / HSF1-dependent transactivation / VEGFA-VEGFR2 Pathway / Attenuation phase / HSF1 activation / Signaling by ERBB2 / HSP90 chaperone cycle for steroid hormone receptors (SHR) / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Scavenging by Class F Receptors / vRNP Assembly / Regulation of PLK1 Activity at G2/M Transition / Sema3A PAK dependent Axon repulsion / VEGFR2 mediated vascular permeability / Chaperone Mediated Autophagy / Estrogen-dependent gene expression / Extra-nuclear estrogen signaling / ESR-mediated signaling / Downregulation of ERBB2 signaling / AURKA Activation by TPX2 / The role of GTSE1 in G2/M progression after G2 checkpoint / Neutrophil degranulation / Uptake and function of diphtheria toxin / Constitutive Signaling by EGFRvIII / Interleukin-4 and Interleukin-13 signaling / PIWI-interacting RNA (piRNA) biogenesis / eNOS activation / Anchoring of the basal body to the plasma membrane / positive regulation of protein polymerization / protein insertion into mitochondrial outer membrane / telomerase holoenzyme complex assembly / mitochondrial transport / chaperone-mediated autophagy / positive regulation of cellular protein catabolic process / central nervous system neuron axonogenesis / TPR domain binding / dendritic growth cone / chaperone-mediated protein complex assembly / telomere maintenance via telomerase / protein unfolding / axon extension / regulation of protein ubiquitination / regulation of protein complex assembly / DNA polymerase binding / regulation of cellular protein localization / positive regulation of tau-protein kinase activity / MHC class II protein complex binding / GTPase binding / protein tyrosine kinase binding / cofactor metabolic process / axonal growth cone / response to unfolded protein / endocytic vesicle lumen / establishment of cell polarity / ciliary basal body-plasma membrane docking / protein folding chaperone / nitric-oxide synthase regulator activity / ATPase activity, coupled / response to cold / positive regulation of telomerase activity / lysosomal lumen / regulation of nitric-oxide synthase activity / ERBB2 signaling pathway / tau protein binding / regulation of cellular response to heat / melanosome / histone deacetylase binding / vascular endothelial growth factor receptor signaling pathway / regulation of G2/M transition of mitotic cell cycle / receptor-mediated endocytosis / Fc-gamma receptor signaling pathway involved in phagocytosis / scaffold protein binding / cellular response to heat / unfolded protein binding / positive regulation of nitric oxide biosynthetic process / myelin sheath / disordered domain specific binding / response to heat / G2/M transition of mitotic cell cycle / positive regulation of peptidyl-serine phosphorylation / protein folding / protein stabilization / protein refolding / secretory granule lumen / ficolin-1-rich granule lumen / ATPase activity / positive regulation of protein phosphorylation / positive regulation of protein kinase B signaling / response to antibiotic / cytokine-mediated signaling pathway / neuronal cell body / ubiquitin protein ligase binding / nucleotide binding / neutrophil degranulation / perinuclear region of cytoplasm / signal transduction
Heat shock hsp90 proteins family signature. / Heat shock protein Hsp90, conserved site / Histidine kinase/HSP90-like ATPase / Heat shock protein Hsp90 family / Ribosomal protein S5 domain 2-type fold / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Hsp90 protein / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Histidine kinase/HSP90-like ATPase superfamily
Heat shock protein HSP 90-alpha
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBrough, P.A. / Barril, X. / Borgognoni, J. / Chene, P. / Davies, N.G.M. / Davis, B. / Drysdale, M.J. / Dymock, B. / Eccles, S.A. / Garcia-Echeverria, C. / Fromont, C. / Hayes, A. / Hubbard, R.E. / Jordan, A.M. / Rugaard-Jensen, M. / Massey, A. / Merret, A. / Padfield, A. / Parsons, R. / Radimerski, T. / Raynaud, F.I. / Robertson, A. / Roughley, S.D. / Schoepfer, J. / Simmonite, H. / Surgenor, A. / Valenti, M. / Walls, S. / Webb, P. / Wood, M. / Workman, P. / Wright, L.M.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Combining Hit Identification Strategies: Fragment- Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-D]Pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.
Authors: Brough, P.A. / Barril, X. / Borgognoni, J. / Chene, P. / Davies, N.G.M. / Davis, B. / Drysdale, M.J. / Dymock, B. / Eccles, S.A. / Garcia-Echeverria, C. / Fromont, C. / Hayes, A. / Hubbard, R.E. / Jordan, A.M. / Jensen, M.R. / Massey, A. / Merrett, A. / Padfield, A. / Parsons, R. / Radimerski, T. / Raynaud, F.I. / Robertson, A. / Roughley, S.D. / Schoepfer, J. / Simmonite, H. / Sharp, S.Y. / Surgenor, A. / Valenti, M. / Walls, S. / Webb, P. / Wood, M. / Workman, P. / Wright, L.M.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMay 8, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 28, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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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)26,7823
Polymers26,6021
Non-polymers1812
Water4,882271
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
γ
α
β
Length a, b, c (Å)65.682, 89.172, 99.783
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein/peptide HEAT SHOCK PROTEIN, HSP 90-ALPHA / Heat shock response / HSP 86 / RENAL CARCINOMA ANTIGEN NY-REN-38


Mass: 26601.773 Da / Num. of mol.: 1 / Fragment: N-TERMINAL ATP-BINDING DOMAIN, RESIDUES 1-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Tissue: MELANOMA / Description: CLONED FROM IMAGE\:4026275 / Organ: SKIN / Plasmid: PET19 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Magnesium
#3: Chemical ChemComp-ZZ3 / 4-METHYL-6-(METHYLSULFANYL)-1,3,5-TRIAZIN-2-AMINE


Mass: 156.209 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H8N4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 271 / Source method: isolated from a natural source / Formula: H2O / Water

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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: 2.8 Å3/Da / Density % sol: 61 % / Description: NONE
Crystal growpH: 6.5 / Details: pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Sep 10, 2002 / Details: OSMIC BLUE MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 21769 / % possible obs: 92.8 % / Observed criterion σ(I): 3 / Redundancy: 2 % / Rmerge(I) obs: 0.02 / Net I/σ(I): 21.2
Reflection shellResolution: 1.9→2.25 Å / Rmerge(I) obs: 0.18 / Mean I/σ(I) obs: 3.2 / % possible all: 64

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Processing

Software
NameVersionClassification
REFMAC5.5.0066refinement
d*TREKdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UY6
Resolution: 1.9→65.94 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.928 / SU B: 2.877 / SU ML: 0.086 / Cross valid method: THROUGHOUT / ESU R: 0.151 / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24248 1114 5.1 %RANDOM
Rwork0.19772 ---
Obs0.19992 20654 92.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.298 Å2
Baniso -1Baniso -2Baniso -3
1--0.26 Å20 Å20 Å2
2--0.6 Å20 Å2
3----0.35 Å2
Refinement stepCycle: LAST / Resolution: 1.9→65.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1628 0 11 271 1910
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0280.0221684
r_bond_other_d
r_angle_refined_deg2.2151.9692277
r_angle_other_deg
r_dihedral_angle_1_deg6.1875213
r_dihedral_angle_2_deg37.86225.26376
r_dihedral_angle_3_deg14.11615309
r_dihedral_angle_4_deg20.503157
r_chiral_restr0.1670.2261
r_gen_planes_refined0.0110.021252
r_gen_planes_other
r_nbd_refined
r_nbd_other
r_nbtor_refined
r_nbtor_other
r_xyhbond_nbd_refined
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined
r_symmetry_vdw_other
r_symmetry_hbond_refined
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_mcbond_it1.3981.51038
r_mcbond_other
r_mcangle_it2.29821679
r_mcangle_other
r_scbond_it3.9623646
r_scbond_other
r_scangle_it5.6894.5595
r_scangle_other
r_long_range_B_refined
r_long_range_B_other
r_rigid_bond_restr
r_sphericity_free
r_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.498 68 -
Rwork0.528 969 -
Obs--61.14 %

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