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- PDB-2yk9: Tricyclic series of Hsp90 inhibitors -

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Basic information

Entry
Database: PDB / ID: 2yk9
TitleTricyclic series of Hsp90 inhibitors
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / INHIBITION
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / telomerase holoenzyme complex assembly / mitochondrial transport / protein insertion into mitochondrial outer membrane / 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 / TPR domain binding / non-chaperonin molecular chaperone ATPase / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / Sema3A PAK dependent Axon repulsion / skeletal muscle contraction / protein unfolding / regulation of postsynaptic membrane neurotransmitter receptor levels / positive regulation of cell size / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / HSF1 activation / telomere maintenance via telomerase / regulation of protein-containing complex assembly / chaperone-mediated protein complex assembly / Attenuation phase / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / axonal growth cone / positive regulation of lamellipodium assembly / DNA polymerase binding / eNOS activation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of defense response to virus by host / Recruitment of mitotic centrosome proteins and complexes / Signaling by ERBB2 / response to salt stress / cardiac muscle cell apoptotic process / positive regulation of telomere maintenance via telomerase / Recruitment of NuMA to mitotic centrosomes / endocytic vesicle lumen / Anchoring of the basal body to the plasma membrane / nitric-oxide synthase regulator activity / positive regulation of cardiac muscle contraction / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / activation of innate immune response / AURKA Activation by TPX2 / positive regulation of interferon-beta production / lysosomal lumen / response to cold / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / protein tyrosine kinase binding / VEGFR2 mediated vascular permeability / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / response to cocaine / brush border membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / tau protein binding / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / cellular response to virus / VEGFA-VEGFR2 Pathway / Downregulation of ERBB2 signaling / histone deacetylase binding / positive regulation of protein import into nucleus / response to estrogen / Chaperone Mediated Autophagy / Aggrephagy / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / disordered domain specific binding / MHC class II protein complex binding / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition
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-like ATPase, C-terminal domain / 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 / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-like ATPase, C-terminal domain / 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 / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
4-(1H-IMIDAZO[4,5-C]PYRIDIN-2-YL)FLUOREN-9-ONE / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.32 Å
AuthorsDupuy, A. / Vallee, F.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone.
Authors: Vallee, F. / Carrez, C. / Pilorge, F. / Dupuy, A. / Parent, A. / Bertin, L. / Thompson, F. / Ferrari, P. / Fassy, F. / Lamberton, A. / Thomas, A. / Arrebola, R. / Guerif, S. / Rohaut, A. / ...Authors: Vallee, F. / Carrez, C. / Pilorge, F. / Dupuy, A. / Parent, A. / Bertin, L. / Thompson, F. / Ferrari, P. / Fassy, F. / Lamberton, A. / Thomas, A. / Arrebola, R. / Guerif, S. / Rohaut, A. / Certal, V. / Ruxer, J.M. / Delorme, C. / Jouanen, A. / Dumas, J. / Grepin, C. / Combeau, C. / Goulaouic, H. / Dereu, N. / Mikol, V. / Mailliet, P. / Minoux, H.
History
DepositionMay 26, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 26, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2011Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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:
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Assembly

Deposited unit
A: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,6592
Polymers23,3611
Non-polymers2971
Water5,657314
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.429, 90.686, 98.734
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-2053-

HOH

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Components

#1: Protein HEAT SHOCK PROTEIN HSP 90-ALPHA / HEAT SHOCK 86 KDA / HSP 86 / HSP86 / RENAL CARCINOMA ANTIGEN NY-REN-38 / HSP90


Mass: 23361.486 Da / Num. of mol.: 1 / Fragment: N-DOMAIN, RESIDUES 18-223
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: P07900
#2: Chemical ChemComp-YK9 / 4-(1H-IMIDAZO[4,5-C]PYRIDIN-2-YL)FLUOREN-9-ONE


Mass: 297.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H11N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 314 / 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: 2.7 Å3/Da / Density % sol: 54.13 % / Description: NONE
Crystal growpH: 7.5 / Details: pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.934
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 31, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 1.32→45.34 Å / Num. obs: 67326 / % possible obs: 95.9 % / Observed criterion σ(I): 2 / Redundancy: 3.8 % / Biso Wilson estimate: 12.05 Å2 / Rmerge(I) obs: 0.04
Reflection shellResolution: 1.32→1.39 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.28 / % possible all: 77

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Processing

Software
NameVersionClassification
BUSTER2.9.7refinement
PROCESSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.32→19.33 Å / Cor.coef. Fo:Fc: 0.9446 / Cor.coef. Fo:Fc free: 0.9409 / SU R Cruickshank DPI: 0.045 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.048 / SU Rfree Blow DPI: 0.047 / SU Rfree Cruickshank DPI: 0.045
Details: REFINEMENT NOTE 1: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY.
RfactorNum. reflection% reflectionSelection details
Rfree0.1953 3392 5.05 %RANDOM
Rwork0.1855 ---
obs0.186 67186 95.82 %-
Displacement parametersBiso mean: 16.16 Å2
Baniso -1Baniso -2Baniso -3
1-1.286 Å20 Å20 Å2
2---0.3255 Å20 Å2
3----0.9605 Å2
Refine analyzeLuzzati coordinate error obs: 0.136 Å
Refinement stepCycle: LAST / Resolution: 1.32→19.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1628 0 23 314 1965
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011681HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.12270HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d596SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes272HARMONIC5
X-RAY DIFFRACTIONt_it1681HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion4.83
X-RAY DIFFRACTIONt_other_torsion14.13
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion229SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2305SEMIHARMONIC4
LS refinement shellResolution: 1.32→1.35 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2199 158 4.27 %
Rwork0.2045 3546 -
all0.2051 3704 -
obs--95.82 %

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