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- PDB-2bz5: Structure-based Discovery of a New Class of Hsp90 Inhibitors -

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Basic information

Entry
Database: PDB / ID: 2bz5
TitleStructure-based Discovery of a New Class of Hsp90 Inhibitors
ComponentsHEAT SHOCK PROTEIN HSP90-ALPHA
KeywordsCHAPERONE / ATP-BINDING / HEAT SHOCK / NUCLEOTIDE-BINDING / PHOSPHORYLATION
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 lamellipodium assembly / axonal growth cone / eNOS activation / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of defense response to virus by host / 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 / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of cardiac muscle contraction / activation of innate immune response / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / AURKA Activation by TPX2 / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / protein tyrosine kinase binding / 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 / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / 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
Chem-AB4 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBarril, X. / Brough, P. / Drysdale, M. / Hubbard, R.E. / Massey, A. / Surgenor, A. / Wright, L.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Structure-Based Discovery of a New Class of Hsp90 Inhibitors.
Authors: Barril, X. / Brough, P. / Drysdale, M. / Hubbard, R.E. / Massey, A. / Surgenor, A. / Wright, L.
History
DepositionAug 11, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 12, 2005Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 31, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name
Revision 1.4Dec 13, 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_conn
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_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)53,8624
Polymers52,9412
Non-polymers9212
Water8,989499
1
A: HEAT SHOCK PROTEIN HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,9312
Polymers26,4711
Non-polymers4601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: HEAT SHOCK PROTEIN HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,9312
Polymers26,4711
Non-polymers4601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)64.460, 88.562, 98.960
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 BL21(DE3) (bacteria) / References: UniProt: P07900
#2: Chemical ChemComp-AB4 / 2,5-DICHLORO-N-[4-HYDROXY-3-(2-HYDROXY-1-NAPHTHYL)PHENYL]BENZENESULFONAMIDE


Mass: 460.330 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H15Cl2NO4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 499 / Source method: isolated from a natural source / Formula: H2O
Compound detailsPROTEIN HAS ATPASE ACTIVITY
Sequence detailsTHE CONFLICT T62S IS ALSO MENTIONED IN THE UNIPROT REFERENCES

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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 %
Crystal growpH: 6.5
Details: CRYSTALLIZATION CONDITIONS: 25% PEG MME 2000, 0.1M NA CACODYLATE, PH6.5, 0.2M MGCL2., pH 6.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418
DetectorType: RIGAKU IMAGE PLATE / Detector: IMAGE PLATE / Date: Mar 10, 2005 / 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: 1.9→30 Å / Num. obs: 40240 / % possible obs: 88.6 % / Observed criterion σ(I): 2 / Redundancy: 3.19 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 11.1
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 2.12 % / Rmerge(I) obs: 0.31 / Mean I/σ(I) obs: 3.1 / % possible all: 56

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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: 0.958 / Cor.coef. Fo:Fc free: 0.932 / SU B: 4.395 / SU ML: 0.119 / Cross valid method: THROUGHOUT / ESU R: 0.162 / ESU R Free: 0.163 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. SLIGHT DISORDER IN THE B-CHAIN BETWEEN RESIDUES 105-112.
RfactorNum. reflection% reflectionSelection details
Rfree0.254 2025 5 %RANDOM
Rwork0.195 ---
obs0.198 38213 88.6 %-
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: 27.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.23 Å20 Å20 Å2
2---0.53 Å20 Å2
3---0.3 Å2
Refinement stepCycle: LAST / Resolution: 1.9→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3303 0 60 499 3862
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0223428
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6521.984629
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8665418
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_restr0.1140.2522
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022534
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.220.21675
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.2372
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2310.263
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1680.231
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9581.52076
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.72623353
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.78631352
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.5614.51276
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
Rfree0.388 75
Rwork0.337 1701

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