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Yorodumi- PDB-2bsm: Novel, potent small molecule inhibitors of the molecular chaperon... -
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-Basic information
Entry | Database: PDB / ID: 2bsm | ||||||
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Title | Novel, potent small molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design | ||||||
Components | HEAT SHOCK PROTEIN HSP90-ALPHA | ||||||
Keywords | CHAPERONE / HSP90 / ATPASE / PU3 / ATP-BINDING / HEAT SHOCK | ||||||
Function / homology | Function and homology information 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 / positive regulation of tau-protein kinase activity / 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 / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / HSF1-dependent transactivation / positive regulation of cell size / response to unfolded protein / telomere maintenance via telomerase / chaperone-mediated protein complex assembly / protein unfolding / 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 / 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 / cardiac muscle cell apoptotic process / positive regulation of defense response to virus by host / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Recruitment of NuMA to mitotic centrosomes / response to salt stress / 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 / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation / cellular response to virus / Downregulation of ERBB2 signaling / VEGFA-VEGFR2 Pathway / histone deacetylase binding / Aggrephagy / positive regulation of protein import into nucleus / Chaperone Mediated Autophagy / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / regulation of protein localization / Regulation of PLK1 Activity at G2/M Transition / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding Similarity search - Function | ||||||
Biological species | HOMO SAPIENS (human) | ||||||
Method | X-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.05 Å | ||||||
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. ...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. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 2bsm.cif.gz | 62.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb2bsm.ent.gz | 44.6 KB | Display | PDB format |
PDBx/mmJSON format | 2bsm.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 2bsm_validation.pdf.gz | 803.2 KB | Display | wwPDB validaton report |
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Full document | 2bsm_full_validation.pdf.gz | 803.9 KB | Display | |
Data in XML | 2bsm_validation.xml.gz | 12.9 KB | Display | |
Data in CIF | 2bsm_validation.cif.gz | 19 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/bs/2bsm ftp://data.pdbj.org/pub/pdb/validation_reports/bs/2bsm | HTTPS FTP |
-Related structure data
Related structure data | 2bt0C 1uy6S S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 26470.578 Da / Num. of mol.: 1 / 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 |
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#2: Chemical | ChemComp-BSM / |
#3: Water | ChemComp-HOH / |
Compound details | FUNCTION: MOLECULAR CHAPERONE. HAS ATPASE ACTIVITY (BY SIMILARITY |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.8 Å3/Da / Density % sol: 56 % |
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Crystal grow | pH: 6.5 Details: 25% PEG MME 2000, 0.1M NA CACODYLATE, PH6.5, 0.2M MGCL2., pH 6.50 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 |
Detector | Type: MARRESEARCH / Detector: IMAGE PLATE / Date: Jan 6, 2003 / Details: OSMIC BLUE MIRRORS |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.5418 Å / Relative weight: 1 |
Reflection | Resolution: 2.05→30 Å / Num. obs: 18512 / % possible obs: 98.5 % / Observed criterion σ(I): 2 / Redundancy: 2.1 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 6.4 |
Reflection shell | Resolution: 2.05→2.12 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 1.6 / % possible all: 93.1 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 1UY6 Resolution: 2.05→30 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.941 / SU B: 5.612 / SU ML: 0.14 / Cross valid method: THROUGHOUT / ESU R: 0.178 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 33.8 Å2
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Refinement step | Cycle: LAST / Resolution: 2.05→30 Å
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