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- PDB-3bmy: Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Hsp90 -

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Entry
Database: PDB / ID: 3bmy
TitleDiscovery of Benzisoxazoles as Potent Inhibitors of Chaperone Hsp90
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / ATP binding domain / Alternative splicing / ATP-binding / Cytoplasm / Nucleotide-binding / Phosphoprotein / Stress response
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / chaperone-mediated autophagy / sperm plasma membrane ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / chaperone-mediated autophagy / sperm plasma membrane / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / telomerase holoenzyme complex assembly / 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 / Uptake and function of diphtheria toxin / protein import into mitochondrial matrix / TPR domain binding / dendritic growth cone / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / protein folding chaperone complex / enzyme-substrate adaptor activity / response to unfolded protein / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / regulation of postsynaptic membrane neurotransmitter receptor levels / axonal growth cone / telomere maintenance via telomerase / skeletal muscle contraction / positive regulation of lamellipodium assembly / nitric oxide metabolic process / response to salt stress / positive regulation of defense response to virus by host / DNA polymerase binding / eNOS activation / positive regulation of telomere maintenance via telomerase / Signaling by ERBB2 / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / cardiac muscle cell apoptotic process / 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 / Recruitment of mitotic centrosome proteins and complexes / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / activation of innate immune response / lysosomal lumen / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of interferon-beta production / protein tyrosine kinase binding / Constitutive Signaling by Overexpressed ERBB2 / response to cold / AURKA Activation by TPX2 / nitric-oxide synthase regulator activity / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / brush border membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / positive regulation of protein import into nucleus / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / response to estrogen / VEGFA-VEGFR2 Pathway / extracellular matrix / tau protein binding / Downregulation of ERBB2 signaling / neuron migration / histone deacetylase binding / Chaperone Mediated Autophagy / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / Aggrephagy
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat Shock Protein 90 / Heat shock protein Hsp90 family / Hsp90 protein / 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. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat Shock Protein 90 / Heat shock protein Hsp90 family / Hsp90 protein / 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-CXZ / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsGopalsamy, A. / Shi, M. / Vogan, E.M. / Golas, J. / Jacob, J. / Johnson, J. / Lee, F. / Nilakantan, R. / Peterson, R. / Svenson, K. ...Gopalsamy, A. / Shi, M. / Vogan, E.M. / Golas, J. / Jacob, J. / Johnson, J. / Lee, F. / Nilakantan, R. / Peterson, R. / Svenson, K. / Tam, M.S. / Wen, Y. / Chopra, R. / Ellingboe, J. / Arndt, K. / Boschelli, F.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery of benzisoxazoles as potent inhibitors of chaperone heat shock protein 90.
Authors: Gopalsamy, A. / Shi, M. / Golas, J. / Vogan, E. / Jacob, J. / Johnson, M. / Lee, F. / Nilakantan, R. / Petersen, R. / Svenson, K. / Chopra, R. / Tam, M.S. / Wen, Y. / Ellingboe, J. / Arndt, K. / Boschelli, F.
History
DepositionDec 13, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 15, 2020Group: Data collection / Database references / Source and taxonomy
Category: entity_src_gen / reflns ...entity_src_gen / reflns / reflns_shell / struct_ref_seq_dif
Item: _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id ..._entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _reflns.pdbx_Rmerge_I_obs / _reflns_shell.number_unique_all / _reflns_shell.number_unique_obs / _struct_ref_seq_dif.details
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 40MOLPROBITY STRUCTURE VALIDATION PROGRAMS: MOLPROBITY (KING, REDUCE, AND PROBE) AUTHORS : I.W. ...MOLPROBITY STRUCTURE VALIDATION PROGRAMS: MOLPROBITY (KING, REDUCE, AND PROBE) AUTHORS : I.W.DAVIS,V.B.CHEN, : R.M.IMMORMINO,J.J.HEADD,W.B.ARENDALL,J.M.WORD REFERENCE : MOLPROBITY: ALL-ATOM CONTACTS AND STRUCTURE : VALIDATION FOR PROTEINS AND NUCLEIC ACIDS : NUCLEIC ACIDS RESEARCH. 2007;35:W375-83.

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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)25,8022
Polymers25,4131
Non-polymers3901
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.721, 42.462, 54.333
Angle α, β, γ (deg.)90.00, 102.22, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Heat shock protein HSP 90-alpha / HSP 86 / Renal carcinoma antigen NY-REN-38


Mass: 25412.568 Da / Num. of mol.: 1 / Fragment: N-terminal domain, UNP residues 10-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Plasmid: pET29A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21DE3 / References: UniProt: P07900
#2: Chemical ChemComp-CXZ / 4-chloro-6-{5-[(2-morpholin-4-ylethyl)amino]-1,2-benzisoxazol-3-yl}benzene-1,3-diol


Mass: 389.833 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H20ClN3O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 2.16 Å3/Da / Density % sol: 43.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 24% PEG 1500, 20% glycerol, pH 7.5, temperature 277K; frozen by 1-step transfer to 18% PEG 1500, 40% glycerol; VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 0.97931 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 30, 2005 / Details: Rosenbaum-Rock vertical focusing mirror
RadiationMonochromator: Rosenbaum-Rock monochromator high-resolution double-crystal Si(220) sagittal focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 1.6→53.074 Å / Num. all: 29139 / Num. obs: 27868 / % possible obs: 95.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Biso Wilson estimate: 15.287 Å2 / Rsym value: 0.083 / Net I/σ(I): 12.8
Reflection shellResolution: 1.6→1.64 Å / Redundancy: 1.9 % / Mean I/σ(I) obs: 3.04 / Num. unique obs: 1958 / Rsym value: 0.261 / % possible all: 65.6

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine)refinement
SERGUIdata collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→53.074 Å / SU ML: 0.19 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): -3 / Phase error: 19.67 / Stereochemistry target values: Engh & Huber
Details: (A) There is weak density for the compound in the binding site. Although the density for the chloro-benzene group is quite strong, the density for the benzisoxazole group becomes weak ...Details: (A) There is weak density for the compound in the binding site. Although the density for the chloro-benzene group is quite strong, the density for the benzisoxazole group becomes weak (approximately half of the group, closest to the chloro-benzene, is well resolved). Finally, density for the morpholine group is very weak, and likely indicates significant mobility of this group. (B) Density for the terminal morpoline group resolved only after a run with autoBuster (with the ligand omited from the structure). A futher run with the ligand roughly positioned but omited from the calculations (-Lpdb) provided the density used to refine the position of the ligand. However, the refined group B-factors for the ligand (~53) indicate that the ligand is highly mobile, and the modeled configuration is likely not the sole conformation of the tail of the compound
RfactorNum. reflection% reflectionSelection details
Rfree0.1961 1377 5.12 %Random
Rwork0.194 ---
obs0.194 27855 95.3 %-
all-29232 --
Displacement parametersBiso mean: 24.54 Å2
Baniso -1Baniso -2Baniso -3
1-1.1206 Å2-0 Å2-6.2313 Å2
2---2.0617 Å2-0 Å2
3----0.184 Å2
Refinement stepCycle: LAST / Resolution: 1.6→53.074 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1678 0 27 199 1904
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.109
X-RAY DIFFRACTIONf_dihedral_angle_d17.709
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)Num. reflection obs
1.6-1.65130.2555910.2498166360
1.6513-1.71740.25091100.2408812230
1.7174-1.79550.21861440.2273912510
1.7955-1.89020.22391300.203952620
1.8902-2.00860.16571310.1978972694
2.0086-2.16370.19091540.1843982713
2.1637-2.38140.17581560.1876992739
2.3814-2.7260.18891470.1854992753
2.726-3.43440.18421660.18341002761
3.4344-47.6390.19891480.18691002857

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