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Yorodumi- PDB-4fcq: Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrr... -
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-Basic information
Entry | Database: PDB / ID: 4fcq | ||||||
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Title | Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization | ||||||
Components | Heat shock protein HSP 90-alphaHeat shock response | ||||||
Keywords | CHAPERONE / Heat Shock Protein / Hsp90 / ATPase / Fragments / Structure-based design. | ||||||
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 / protein insertion into mitochondrial outer membrane / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / 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 / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / skeletal muscle contraction / protein unfolding / regulation of protein-containing complex assembly / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / HSF1 activation / chaperone-mediated protein complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / DNA polymerase binding / positive regulation of lamellipodium assembly / axonal growth cone / eNOS activation / endocytic vesicle lumen / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / positive regulation of defense response to virus by host / Signaling by ERBB2 / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / response to salt stress / positive regulation of telomerase activity / Recruitment of NuMA to mitotic centrosomes / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein tyrosine kinase binding / Anchoring of the basal body to the plasma membrane / positive regulation of interferon-beta production / activation of innate immune response / response to cold / nitric-oxide synthase regulator activity / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / AURKA Activation by TPX2 / response to cocaine / VEGFR2 mediated vascular permeability / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / tau protein binding / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / cellular response to virus / VEGFA-VEGFR2 Pathway / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / histone deacetylase binding / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / positive regulation of nitric oxide biosynthetic process / regulation of protein localization / disordered domain specific binding / Regulation of PLK1 Activity at G2/M Transition / melanosome / unfolded protein binding Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.151 Å | ||||||
Authors | Davies, N.G. / Browne, H. / Davis, B. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Drysdale, M.J. / Mansell, H. / Massey, A. ...Davies, N.G. / Browne, H. / Davis, B. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Drysdale, M.J. / Mansell, H. / Massey, A. / Matassova, N. / Moore, J.D. / Murray, J. / Pratt, R. / Ray, S. / Roughley, S.D. / Jensen, M.R. / Schoepfer, J. / Scriven, K. / Simmonite, H. / Stokes, S. / Surgenor, A. / Webb, P. / Wright, L. / Brough, P. | ||||||
Citation | Journal: Bioorg.Med.Chem. / Year: 2012 Title: Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization. Authors: Davies, N.G. / Browne, H. / Davis, B. / Drysdale, M.J. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Hubbard, R. / Jensen, M.R. / Mansell, H. / Massey, A. / Matassova, N. / Moore, ...Authors: Davies, N.G. / Browne, H. / Davis, B. / Drysdale, M.J. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Hubbard, R. / Jensen, M.R. / Mansell, H. / Massey, A. / Matassova, N. / Moore, J.D. / Murray, J. / Pratt, R. / Ray, S. / Robertson, A. / Roughley, S.D. / Schoepfer, J. / Scriven, K. / Simmonite, H. / Stokes, S. / Surgenor, A. / Webb, P. / Wood, M. / Wright, L. / Brough, P. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4fcq.cif.gz | 58.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4fcq.ent.gz | 42.3 KB | Display | PDB format |
PDBx/mmJSON format | 4fcq.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fc/4fcq ftp://data.pdbj.org/pub/pdb/validation_reports/fc/4fcq | HTTPS FTP |
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-Related structure data
Related structure data | 4fcpC 4fcrC 1uy6S C: citing same article (ref.) S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 26601.773 Da / Num. of mol.: 1 / Fragment: UNP Residues 1-236 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Plasmid: PET19 / Production host: Escherichia coli (E. coli) / Strain (production host): Bl21(DE3) / References: UniProt: P07900 |
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#2: Chemical | ChemComp-2N6 / |
#3: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.66 Å3/Da / Density % sol: 53.83 % |
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Crystal grow | Temperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 Details: 25% PEG MME 2000, 0.1M Na Cacodylate, PH6.5, 0.2M MGCl2, VAPOR DIFFUSION, HANGING DROP, temperature 298K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.02 Å |
Detector | Type: ADSC QUANTUM 4r / Detector: CCD / Date: Sep 25, 2006 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.02 Å / Relative weight: 1 |
Reflection | Resolution: 2.15→30 Å / Num. all: 32907 / Num. obs: 15870 / % possible obs: 87.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.057 |
Reflection shell | Resolution: 2.15→2.22 Å / % possible all: 84.1 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 1UY6 Resolution: 2.151→26.73 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.932 / SU B: 5.675 / SU ML: 0.145 / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 2 / ESU R: 0.25 / ESU R Free: 0.216 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 45.267 Å2
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Refinement step | Cycle: LAST / Resolution: 2.151→26.73 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.151→2.206 Å / Total num. of bins used: 20
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