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- PDB-2yk2: Tricyclic series of Hsp90 inhibitors -

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Basic information

Entry
Database: PDB / ID: 2yk2
TitleTricyclic series of Hsp90 inhibitors
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / INHIBITION
Function / homology
Function and homology information


sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding ...sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / mitochondrial transport / negative regulation of striated muscle cell apoptotic process / HSP90-CDC37 chaperone complex / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / AP-3 adaptor complex binding / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / 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 / Uptake and function of diphtheria toxin / positive regulation of cell size / dendritic growth cone / TPR domain binding / protein import into mitochondrial matrix / PIWI-interacting RNA (piRNA) biogenesis / response to dietary excess / response to caloric restriction / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / Sema3A PAK dependent Axon repulsion / response to salt stress / regulation of protein ubiquitination / response to unfolded protein / HSF1-dependent transactivation / cardiac muscle cell apoptotic process / regulation of protein-containing complex assembly / Attenuation phase / protein folding chaperone complex / HSF1 activation / enzyme-substrate adaptor activity / chaperone-mediated protein complex assembly / axonal growth cone / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / positive regulation of lamellipodium assembly / RHOBTB2 GTPase cycle / Dengue virus activates/modulates innate and adaptive immune responses / nitric oxide metabolic process / response to isolation stress / protein unfolding / positive regulation of defense response to virus by host / skeletal muscle contraction / Signaling by ERBB2 / eNOS activation / positive regulation of telomere maintenance via telomerase / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / response to cold / endocytic vesicle lumen / DNA polymerase binding / 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 / cellular response to platelet-derived growth factor stimulus / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / ESR-mediated signaling / Anchoring of the basal body to the plasma membrane / activation of innate immune response / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / nitric-oxide synthase regulator activity / response to cocaine / ATP-dependent protein folding chaperone / VEGFR2 mediated vascular permeability / brush border membrane / cellular response to virus / positive regulation of protein import into nucleus / neuron migration / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / protein refolding / Regulation of actin dynamics for phagocytic cup formation / Signaling by ERBB2 KD Mutants / response to estrogen / VEGFA-VEGFR2 Pathway
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, DNA gyrase B-, and HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, 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
Chem-YJW / Chem-YJX / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.74 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 25, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 19, 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:
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)23,9313
Polymers23,3611
Non-polymers5702
Water5,224290
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.608, 99.103, 90.873
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-2043-

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-YJW / 4-(5-METHYL-4-PHENYLISOXAZOL-3-YL)BENZENE-1,3-DIOL


Mass: 267.279 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13NO3
#3: Chemical ChemComp-YJX / 1-(3H-imidazo[4,5-c]pyridin-2-yl)-3,4-dihydropyrido[2,1-a]isoindol-6(2H)-one


Mass: 302.330 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14N4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 290 / 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: 3.21 Å3/Da / Density % sol: 61.68 % / Description: NONE
Crystal growpH: 7.5 / Details: pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 6, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.74→14.85 Å / Num. obs: 30793 / % possible obs: 98.6 % / Observed criterion σ(I): 2 / Redundancy: 3.5 % / Biso Wilson estimate: 22.18 Å2 / Rmerge(I) obs: 0.07
Reflection shellResolution: 1.74→1.8 Å / Rmerge(I) obs: 0.38 / % possible all: 90.9

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Processing

Software
NameVersionClassification
BUSTER2.9.7refinement
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.74→14.85 Å / Cor.coef. Fo:Fc: 0.9504 / Cor.coef. Fo:Fc free: 0.9335 / SU R Cruickshank DPI: 0.093 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.101 / SU Rfree Blow DPI: 0.098 / SU Rfree Cruickshank DPI: 0.093
RfactorNum. reflection% reflectionSelection details
Rfree0.2111 1558 5.08 %RANDOM
Rwork0.1815 ---
obs0.183 30660 98.36 %-
Displacement parametersBiso mean: 24.38 Å2
Baniso -1Baniso -2Baniso -3
1--0.0181 Å20 Å20 Å2
2---0.1729 Å20 Å2
3---0.191 Å2
Refine analyzeLuzzati coordinate error obs: 0.186 Å
Refinement stepCycle: LAST / Resolution: 1.74→14.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1628 0 43 290 1961
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011703HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.012301HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d603SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes291HARMONIC5
X-RAY DIFFRACTIONt_it1703HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.48
X-RAY DIFFRACTIONt_other_torsion16.66
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_contact2311SEMIHARMONIC4
LS refinement shellResolution: 1.74→1.8 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2529 154 5.94 %
Rwork0.2386 2439 -
all0.2394 2593 -
obs--98.36 %

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