- PDB-3bmy: Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Hsp90 -
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Open data
ID or keywords:
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Basic information
Entry
Database: PDB / ID: 3bmy
Title
Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Hsp90
Components
Heat shock protein HSP 90-alpha
Keywords
CHAPERONE / ATP binding domain / Alternative splicing / ATP-binding / Cytoplasm / Nucleotide-binding / Phosphoprotein / Stress response
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 / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / protein insertion into mitochondrial outer membrane / 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 / Signaling by ERBB2 / telomere maintenance via telomerase / HSF1-dependent transactivation / positive regulation of cell size / response to unfolded protein / protein unfolding / chaperone-mediated protein complex assembly / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / eNOS activation / axonal growth cone / positive regulation of lamellipodium assembly / 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 / cardiac muscle cell apoptotic process / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / response to salt stress / positive regulation of cardiac muscle contraction / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / activation of innate immune response / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / lysosomal lumen / ESR-mediated signaling / protein tyrosine kinase binding / Signaling by ERBB2 TMD/JMD mutants / VEGFR2 mediated vascular permeability / Constitutive Signaling by EGFRvIII / response to cocaine / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / brush border membrane / ATP-dependent protein folding chaperone / Downregulation of ERBB2 signaling / neuron migration / DDX58/IFIH1-mediated induction of interferon-alpha/beta / tau protein binding / Regulation of necroptotic cell death / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / histone deacetylase binding / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / regulation of protein localization / disordered domain specific binding / Regulation of PLK1 Activity at G2/M Transition / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of nitric oxide biosynthetic process 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
Resolution: 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
Name
Version
Classification
PHENIX
(phenix.refine)
refinement
SERGUI
datacollection
HKL-2000
datareduction
HKL-2000
datascaling
PHASER
phasing
Refinement
Method 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
Rfactor
Num. reflection
% reflection
Selection details
Rfree
0.1961
1377
5.12 %
Random
Rwork
0.194
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obs
0.194
27855
95.3 %
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all
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29232
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Displacement parameters
Biso mean: 24.54 Å2
Baniso -1
Baniso -2
Baniso -3
1-
1.1206 Å2
-0 Å2
-6.2313 Å2
2-
-
-2.0617 Å2
-0 Å2
3-
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-0.184 Å2
Refinement step
Cycle: LAST / Resolution: 1.6→53.074 Å
Protein
Nucleic acid
Ligand
Solvent
Total
Num. atoms
1678
0
27
199
1904
Refine LS restraints
Refine-ID
Type
Dev ideal
X-RAY DIFFRACTION
f_bond_d
0.008
X-RAY DIFFRACTION
f_angle_d
1.109
X-RAY DIFFRACTION
f_dihedral_angle_d
17.709
LS refinement shell
Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10
Resolution (Å)
Rfactor Rfree
Num. reflection Rfree
Rfactor Rwork
Num. reflection Rwork
% reflection obs (%)
Num. reflection obs
1.6-1.6513
0.2555
91
0.2498
1663
60
1.6513-1.7174
0.2509
110
0.2408
81
2230
1.7174-1.7955
0.2186
144
0.2273
91
2510
1.7955-1.8902
0.2239
130
0.203
95
2620
1.8902-2.0086
0.1657
131
0.1978
97
2694
2.0086-2.1637
0.1909
154
0.1843
98
2713
2.1637-2.3814
0.1758
156
0.1876
99
2739
2.3814-2.726
0.1889
147
0.1854
99
2753
2.726-3.4344
0.1842
166
0.1834
100
2761
3.4344-47.639
0.1989
148
0.1869
100
2857
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