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- PDB-2wi2: Orally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Ch... -

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Entry
Database: PDB / ID: 2wi2
TitleOrally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Chaperone
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / PU3 / HSP90 / ATPASE / HEAT SHOCK / STRESS RESPONSE / NUCLEOTIDE-BINDING / ATP-BINDING / PHOSPHOPROTEIN / PHOSPHORYLATION
Function / homology
Function and homology information


positive regulation of tau-protein kinase activity / sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane ...positive regulation of tau-protein kinase activity / sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / Uptake and function of diphtheria toxin / mitochondrial transport / 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 / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / regulation of postsynaptic membrane neurotransmitter receptor levels / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / telomere maintenance via telomerase / protein unfolding / HSF1-dependent transactivation / response to unfolded protein / positive regulation of cell size / chaperone-mediated protein complex assembly / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / axonal growth cone / eNOS activation / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of defense response to virus by host / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Signaling by ERBB2 / response to salt stress / cardiac muscle cell apoptotic process / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of cardiac muscle contraction / activation of innate immune response / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / AURKA Activation by TPX2 / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / protein tyrosine kinase binding / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / neuron migration / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / tau protein binding / Regulation of necroptotic cell death / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Aggrephagy / Chaperone Mediated Autophagy / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding / melanosome
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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 / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / 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 / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
4-METHYL-6-(METHYLSULFANYL)-1,3,5-TRIAZIN-2-AMINE / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.09 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. ...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. / 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, ...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.
History
DepositionMay 8, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 28, 2009Provider: repository / Type: Initial release
Revision 1.1Aug 10, 2011Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Refinement description / Structure summary / Version format compliance
Revision 1.2Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _pdbx_database_status.status_code_sf / _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: HEAT SHOCK PROTEIN HSP 90-ALPHA
B: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,5945
Polymers53,2042
Non-polymers3913
Water4,288238
1
A: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,8363
Polymers26,6021
Non-polymers2342
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7582
Polymers26,6021
Non-polymers1561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.271, 88.442, 98.589
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein HEAT SHOCK PROTEIN HSP 90-ALPHA / HSP 86 / RENAL CARCINOMA ANTIGEN NY-REN-38


Mass: 26601.773 Da / Num. of mol.: 2 / 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-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-ZZ3 / 4-METHYL-6-(METHYLSULFANYL)-1,3,5-TRIAZIN-2-AMINE


Mass: 156.209 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H8N4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 238 / 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: 2.9 Å3/Da / Density % sol: 55.3 % / 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 R-AXIS IV / Detector: IMAGE PLATE / Date: Jul 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: 2.09→30 Å / Num. obs: 31480 / % possible obs: 92.3 % / Observed criterion σ(I): 3 / Redundancy: 2 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 6
Reflection shellResolution: 2.09→2.8 Å / Redundancy: 2 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 1.8 / % possible all: 58.3

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Processing

Software
NameVersionClassification
REFMAC5.5.0066refinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UY6

1uy6


Resolution: 2.09→100 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.905 / SU B: 5.297 / SU ML: 0.142 / Cross valid method: THROUGHOUT / ESU R: 0.245 / ESU R Free: 0.217 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.28858 1579 5 %RANDOM
Rwork0.23658 ---
obs0.23917 29841 92.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.362 Å2
Baniso -1Baniso -2Baniso -3
1--0.21 Å20 Å20 Å2
2---0.91 Å20 Å2
3---1.12 Å2
Refinement stepCycle: LAST / Resolution: 2.09→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3260 0 24 238 3522
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0223342
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9861.9714509
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0575416
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.72525.135148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.78515612
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.1091514
X-RAY DIFFRACTIONr_chiral_restr0.1320.2518
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022468
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.9971.52062
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.72223331
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.10631280
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.9294.51177
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: 2.089→2.144 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.42 74 -
Rwork0.381 1334 -
obs--56.01 %

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