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- PDB-2ye9: HSP90 inhibitors and drugs from fragment and virtual screening -

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Basic information

Entry
Database: PDB / ID: 2ye9
TitleHSP90 inhibitors and drugs from fragment and virtual screening
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / PU3 / ATPASE / STRESS RESPONSE / NUCLEOTIDE-BINDING / ATP-BINDING / PHOSPHOPROTEIN / PHOSPHORYLATION
Function / homology
Function and homology information


sulfonylurea receptor binding / sperm mitochondrial sheath / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sulfonylurea receptor binding / sperm mitochondrial sheath / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / mitochondrial transport / 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 / protein insertion into mitochondrial outer membrane / TPR domain binding / dendritic growth cone / Assembly and release of respiratory syncytial virus (RSV) virions / PIWI-interacting RNA (piRNA) biogenesis / non-chaperonin molecular chaperone ATPase / Sema3A PAK dependent Axon repulsion / protein unfolding / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / HSF1 activation / skeletal muscle contraction / regulation of protein-containing complex assembly / axonal growth cone / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / DNA polymerase binding / positive regulation of defense response to virus by host / response to salt stress / Signaling by ERBB2 / positive regulation of telomere maintenance via telomerase / cardiac muscle cell apoptotic process / positive regulation of cardiac muscle contraction / endocytic vesicle lumen / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / activation of innate immune response / Recruitment of NuMA to mitotic centrosomes / lysosomal lumen / Anchoring of the basal body to the plasma membrane / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / ESR-mediated signaling / protein tyrosine kinase binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / Regulation of actin dynamics for phagocytic cup formation / cellular response to virus / Regulation of necroptotic cell death / tau protein binding / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / response to estrogen / Downregulation of ERBB2 signaling / histone deacetylase binding / neuron migration / Chaperone Mediated Autophagy / positive regulation of protein catabolic process / Aggrephagy / positive regulation of nitric oxide biosynthetic process / MHC class II protein complex binding / disordered domain specific binding
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/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/HSP90-like ATPase / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-2D4 / 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 1.1Aug 31, 2011Group: Database references / Version format compliance
Revision 1.2Dec 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)28,9212
Polymers28,5241
Non-polymers3971
Water2,378132
1
A: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules

A: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,8434
Polymers57,0482
Non-polymers7952
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area1530 Å2
ΔGint-12.7 kcal/mol
Surface area18860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.245, 89.568, 100.420
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 HEAT SHOCK PROTEIN HSP 90-ALPHA / HEAT SHOCK 86 KDA / RENAL CARCINOMA ANTIGEN NY-REN-38 / HSP 86 / HSP86


Mass: 28523.869 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 / Organ: SKIN / Plasmid: PET19 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-2D4 / N-[4-HYDROXY-3-(2-HYDROXYNAPHTHALEN-1-YL)PHENYL]THIOPHENE-2-SULFONAMIDE


Mass: 397.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15NO4S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / 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: 2.61 Å3/Da / Density % sol: 52.89 % / 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: Nov 6, 2002 / 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→67.42 Å / Num. obs: 13358 / % possible obs: 95.4 % / Observed criterion σ(I): 2 / Redundancy: 2 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 5
Reflection shellResolution: 2.2→2.26 Å / Rmerge(I) obs: 0.44 / % possible all: 96.6

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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→67.42 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.895 / SU B: 6.429 / SU ML: 0.163 / Cross valid method: THROUGHOUT / ESU R: 0.275 / ESU R Free: 0.245 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.28919 1495 10.1 %RANDOM
Rwork0.22067 ---
obs0.22748 13358 95.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.894 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20 Å20 Å2
2---0.25 Å20 Å2
3---0.17 Å2
Refinement stepCycle: LAST / Resolution: 2.2→67.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1628 0 27 132 1787
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0221691
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.891.9832287
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2645209
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.74724.79573
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.57615306
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20158
X-RAY DIFFRACTIONr_chiral_restr0.1280.2261
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021251
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_it0.981.51034
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.82221673
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.0913657
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.034.5613
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: 2.198→2.255 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.441 111 -
Rwork0.319 963 -
obs--96.58 %

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