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- PDB-3bm9: Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Hsp90 -

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Basic information

Entry
Database: PDB / ID: 3bm9
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 / 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 / Uptake and function of diphtheria toxin / protein insertion into mitochondrial outer membrane / 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 / enzyme-substrate adaptor activity / 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 / 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 / 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 / Recruitment of NuMA to mitotic centrosomes / activation of innate immune response / Anchoring of the basal body to the plasma membrane / lysosomal lumen / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / response to cold / 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 / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / 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 / tau protein binding / 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 / neuron migration / Aggrephagy / disordered domain specific binding / MHC class II protein complex binding / The role of GTSE1 in G2/M progression after G2 checkpoint
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-BXZ / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / 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 12, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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 AUTHORS : I.W.DAVIS,A.LEAVER-FAY,V.B.CHEN,J.N.BLOCK, : G.J.KAPRAL,X.WANG,L.W.MURRAY,W.B.ARENDALL, : J.SNOEYINK,J.S.RICHARDSON,D.C.RICHARDSON 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)25,7352
Polymers25,4131
Non-polymers3221
Water6,395355
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.089, 89.033, 100.172
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-367-

HOH

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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: pET28A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21DE3 / References: UniProt: P07900
#2: Chemical ChemComp-BXZ / 4-bromo-6-(6-hydroxy-1,2-benzisoxazol-3-yl)benzene-1,3-diol


Mass: 322.111 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H8BrNO4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 355 / 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: 2.9 Å3/Da / Density % sol: 57.58 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 20% PEG3350, 0.2M MAGNESIUM ACETATE, PH 7.5, TEMPERATURE 277K; FROZEN BY 1-STEP TRANSFER TO 25% GLYCEROL, 15% PEG3350, 0.15M MAGNESIUM ACETATE, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Dec 12, 2007 / Details: mirrors
RadiationMonochromator: Osmic mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.6→34.65 Å / Num. all: 39219 / Num. obs: 36317 / % possible obs: 92.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 9.2 % / Biso Wilson estimate: 14.785 Å2 / Rsym value: 0.055 / Net I/σ(I): 26.4
Reflection shellResolution: 1.6→1.64 Å / Redundancy: 1.6 % / Mean I/σ(I) obs: 3.3 / Num. unique all: 2592 / Rsym value: 0.208 / % possible all: 59.8

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine)refinement
StructureStudiodata collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→34.65 Å / SU ML: 0.15 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): -3 / Phase error: 18 / Stereochemistry target values: Engh & Huber
Details: LIGAND BXZ OCCUPANCY WAS REFINED AS A SINGLE GROUP TO 0.85. FOLLOWING THIS REFINEMENT, THE OCCUPANCY OF THE BROMINE ATOM WAS ADJUSTED TO 0.70 BASED ON RESIDUAL MAPS. RESIDUES 155 to 157 SHOW ...Details: LIGAND BXZ OCCUPANCY WAS REFINED AS A SINGLE GROUP TO 0.85. FOLLOWING THIS REFINEMENT, THE OCCUPANCY OF THE BROMINE ATOM WAS ADJUSTED TO 0.70 BASED ON RESIDUAL MAPS. RESIDUES 155 to 157 SHOW TWO (MAINCHAIN) CONFORMATIONS, BUT ONLY THE MAJOR CONFORMATION WAS MODELED
RfactorNum. reflection% reflectionSelection details
Rfree0.1861 1744 5.03 %Random
Rwork0.1635 ---
all0.1646 39211 --
obs0.1646 36282 92.4 %-
Displacement parametersBiso mean: 20.11 Å2
Baniso -1Baniso -2Baniso -3
1--2.2099 Å20 Å20 Å2
2--1.2539 Å20 Å2
3---0.9561 Å2
Refinement stepCycle: LAST / Resolution: 1.6→34.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1662 0 19 355 2036
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONf_bond_d0.004
X-RAY DIFFRACTIONf_angle_d0.924
X-RAY DIFFRACTIONf_dihedral_angle_d15.044
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection Rwork% reflection obs (%)Num. reflection obs
1.6-1.64830.194794.5560.1782165554
1.6483-1.70150.2396960.1806722232
1.7015-1.76240.211300.1759802462
1.7624-1.83290.22761240.1717842572
1.8329-1.91630.17291390.16872700
1.9163-2.01740.19361690.1658942895
2.0174-2.14370.16971580.1572983013
2.1437-2.30920.18311560.1522983019
2.3092-2.54150.17271770.1661983011
2.5415-2.90910.19491680.1678983051
2.9091-3.66460.17641720.1564993112
3.6646-34.650.18011760.1538993236

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