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- PDB-2yei: HSP90 inhibitors and drugs from fragment and virtual screening -

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Basic information

Entry
Database: PDB / ID: 2yei
TitleHSP90 inhibitors and drugs from fragment and virtual screening
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / STRESS RESPONSE
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 defense response to virus by host / eNOS activation / positive regulation of lamellipodium assembly / axonal growth cone / DNA polymerase binding / activation of innate immune response / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / 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 / positive regulation of cardiac muscle contraction / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / protein tyrosine kinase binding / AURKA Activation by TPX2 / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / 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 / Regulation of PLK1 Activity at G2/M Transition / positive regulation of nitric oxide biosynthetic process / 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
METHYL 2-(3,5-DIHYDROXYPHENYL)ETHANOATE / Chem-XQK / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsRoughley, S.D. / Hubbard, R.E. / Baker, L.M.
CitationJournal: J.Med.Chem. / Year: 2011
Title: How Well Can Fragments Explore Accessed Chemical Space? a Case Study from Heat Shock Protein 90.
Authors: Roughley, S.D. / Hubbard, R.E.
History
DepositionMar 25, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2011Provider: repository / Type: Initial release
Revision 1.1Jun 23, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 20, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)28,9223
Polymers28,5331
Non-polymers3892
Water4,432246
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.801, 90.319, 98.229
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-2037-

HOH

21A-2038-

HOH

31A-2047-

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


Mass: 28532.904 Da / Num. of mol.: 1 / Fragment: N-TERMINAL ATP-BINDING DOMAIN, RESIDUES 9-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Organ: SKIN / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-XQK / METHYL 5-ISOXAZOL-5-YL-3-METHYL-1H-PYRAZOLE-4-CARBOXYLATE


Mass: 207.186 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H9N3O3
#3: Chemical ChemComp-XQI / METHYL 2-(3,5-DIHYDROXYPHENYL)ETHANOATE


Mass: 182.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H10O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 246 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsRESIDUE 1 IN THE UNIPROT SEQUENCE IS AN INITIATOR METHIONINE AND IS REMOVED.

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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: 56.04 % / 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: May 12, 2003 / Details: OSMIC BLUE MIRRORS
RadiationMonochromator: CU FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→65.94 Å / Num. obs: 12939 / % possible obs: 88.1 % / Observed criterion σ(I): 1 / Redundancy: 2 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 4.3
Reflection shellResolution: 2.2→2.26 Å / Rmerge(I) obs: 0.4 / % possible all: 91.2

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WI1

2wi1


Resolution: 2.2→65.94 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.794 / SU B: 14.086 / SU ML: 0.341 / Cross valid method: THROUGHOUT / ESU R: 0.355 / ESU R Free: 0.35 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.38953 677 5 %RANDOM
Rwork0.25176 ---
obs0.25854 12939 88.07 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.346 Å2
Baniso -1Baniso -2Baniso -3
1--0.86 Å20 Å20 Å2
2--0.25 Å20 Å2
3---0.61 Å2
Refinement stepCycle: LAST / Resolution: 2.2→65.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1637 0 28 246 1911
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0221701
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8251.9792295
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.4435207
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.46725.13276
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.48815311
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.575157
X-RAY DIFFRACTIONr_chiral_restr0.1260.2260
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021264
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_it0.7361.51029
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.37621667
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.9473672
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.1064.5628
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: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.395 50 -
Rwork0.348 975 -
obs--91.19 %

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