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Basic information

Entry
Database: PDB / ID: 2bt0
TitleNovel, potent small molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design
ComponentsHEAT SHOCK PROTEIN HSP90-ALPHA
KeywordsCHAPERONE / ATP-BINDING / HEAT SHOCK / PHOSPHORYLATION
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 / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / 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 / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / dendritic growth cone / Sema3A PAK dependent Axon repulsion / protein unfolding / positive regulation of cell size / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / skeletal muscle contraction / regulation of postsynaptic membrane neurotransmitter receptor levels / regulation of protein-containing complex assembly / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / 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 / cardiac muscle cell apoptotic process / positive regulation of telomere maintenance via telomerase / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / nitric-oxide synthase regulator activity / Recruitment of mitotic centrosome proteins and complexes / activation of innate immune response / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / lysosomal lumen / positive regulation of interferon-beta production / response to cold / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / ESR-mediated signaling / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / ATP-dependent protein folding chaperone / response to cocaine / neuron migration / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Downregulation of ERBB2 signaling / response to estrogen / Chaperone Mediated Autophagy / positive regulation of protein catabolic process / Aggrephagy / disordered domain specific binding / MHC class II protein complex binding / The role of GTSE1 in G2/M progression after G2 checkpoint / 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
Chem-CT5 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsDymock, B.W. / Barril, X. / Brough, P.A. / Cansfield, J.E. / Massey, A. / McDonald, E. / Hubbard, R.E. / Surgenor, A. / Roughley, S.D. / Webb, P. ...Dymock, B.W. / Barril, X. / Brough, P.A. / Cansfield, J.E. / Massey, A. / McDonald, E. / Hubbard, R.E. / Surgenor, A. / Roughley, S.D. / Webb, P. / Workman, P. / Wright, L. / Drysdale, M.J.
CitationJournal: J. Med. Chem. / Year: 2005
Title: Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.
Authors: Dymock, B.W. / Barril, X. / Brough, P.A. / Cansfield, J.E. / Massey, A. / McDonald, E. / Hubbard, R.E. / Surgenor, A. / Roughley, S.D. / Webb, P. / Workman, P. / Wright, L. / Drysdale, M.J.
History
DepositionMay 24, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 2, 2005Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 28, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.page_last ..._citation.journal_abbrev / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name
Revision 1.4Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HEAT SHOCK PROTEIN HSP90-ALPHA
B: HEAT SHOCK PROTEIN HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,6464
Polymers52,9412
Non-polymers7052
Water8,773487
1
A: HEAT SHOCK PROTEIN HSP90-ALPHA
hetero molecules

A: HEAT SHOCK PROTEIN HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,6464
Polymers52,9412
Non-polymers7052
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
MethodPQS
2
B: HEAT SHOCK PROTEIN HSP90-ALPHA
hetero molecules

B: HEAT SHOCK PROTEIN HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,6464
Polymers52,9412
Non-polymers7052
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
MethodPQS
Unit cell
Length a, b, c (Å)64.188, 88.508, 98.549
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 HSP90-ALPHA / HSP 86


Mass: 26470.578 Da / Num. of mol.: 2 / Fragment: N-TERMINAL DOMAIN, RESIDUES 1-235
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-CT5 / 4-[4-(2,3-DIHYDRO-1,4-BENZODIOXIN-6-YL)-3-METHYL-1H-PYRAZOL-5-YL]-6-ETHYLBENZENE-1,3-DIOL


Mass: 352.384 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N2O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 487 / Source method: isolated from a natural source / Formula: H2O
Compound detailsFUNCTION: ATPASE ACTIVITY
Sequence detailsTHE CONFLICT IS ALSO MENTIONED IN UNP

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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: 57.5 %
Crystal growpH: 6.5 / Details: pH 6.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Aug 4, 2004 / 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→30 Å / Num. obs: 19136 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 3.42 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 10.6
Reflection shellResolution: 2→2.07 Å / Redundancy: 2.44 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 3.4 / % possible all: 93

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UY6

1uy6


Resolution: 1.9→30 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.929 / SU B: 4.498 / SU ML: 0.121 / Cross valid method: THROUGHOUT / ESU R: 0.154 / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.244 2170 5.1 %RANDOM
Rwork0.202 ---
obs0.204 40741 95.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 18.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.39 Å20 Å20 Å2
2--0.3 Å20 Å2
3----0.69 Å2
Refinement stepCycle: LAST / Resolution: 1.9→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3272 0 52 487 3811
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0223407
X-RAY DIFFRACTIONr_bond_other_d0.0020.023050
X-RAY DIFFRACTIONr_angle_refined_deg1.2791.9414597
X-RAY DIFFRACTIONr_angle_other_deg1.3812.9997136
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1875414
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0760.2517
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023747
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02648
X-RAY DIFFRACTIONr_nbd_refined0.1910.2728
X-RAY DIFFRACTIONr_nbd_other0.2370.23773
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0840.22030
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1520.2364
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1260.210
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2920.249
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2050.219
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.621.52058
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.1523332
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.70731349
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.8954.51265
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: 1.9→1.95 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.352 109
Rwork0.319 2158

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