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Yorodumi- PDB-5m4e: Application of Off-Rate Screening in the Identification of Novel ... -
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-Basic information
Entry | Database: PDB / ID: 5m4e | ||||||
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Title | Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase | ||||||
Components | Heat shock protein HSP 90-alphaHeat shock response | ||||||
Keywords | TRANSFERASE / Off-Rate Screening / PDHK / HSP90 / SPR / kinase inhibitors / fragment screening / cancer / PDK1 / PDK2 / PDK3 / PDK4 | ||||||
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 / chaperone-mediated protein complex assembly / HSF1 activation / 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 / 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 / positive regulation of cardiac muscle contraction / cardiac muscle cell apoptotic process / Recruitment of mitotic centrosome proteins and complexes / Signaling by ERBB2 / 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 / activation of innate immune response / positive regulation of interferon-beta production / response to cold / nitric-oxide synthase regulator activity / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / ESR-mediated signaling / 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 / histone deacetylase binding / response to estrogen / 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 / melanosome / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å | ||||||
Authors | Baker, L.M. | ||||||
Citation | Journal: J. Med. Chem. / Year: 2017 Title: Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase. Authors: Brough, P.A. / Baker, L. / Bedford, S. / Brown, K. / Chavda, S. / Chell, V. / D'Alessandro, J. / Davies, N.G. / Davis, B. / Le Strat, L. / Macias, A.T. / Maddox, D. / Mahon, P.C. / Massey, A. ...Authors: Brough, P.A. / Baker, L. / Bedford, S. / Brown, K. / Chavda, S. / Chell, V. / D'Alessandro, J. / Davies, N.G. / Davis, B. / Le Strat, L. / Macias, A.T. / Maddox, D. / Mahon, P.C. / Massey, A.J. / Matassova, N. / McKenna, S. / Meissner, J.W. / Moore, J.D. / Murray, J.B. / Northfield, C.J. / Parry, C. / Parsons, R. / Roughley, S.D. / Shaw, T. / Simmonite, H. / Stokes, S. / Surgenor, A. / Stefaniak, E. / Robertson, A. / Wang, Y. / Webb, P. / Whitehead, N. / Wood, M. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5m4e.cif.gz | 64.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5m4e.ent.gz | 45.2 KB | Display | PDB format |
PDBx/mmJSON format | 5m4e.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/m4/5m4e ftp://data.pdbj.org/pub/pdb/validation_reports/m4/5m4e | HTTPS FTP |
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-Related structure data
Related structure data | 5m4hC 5m4kC 5m4mC 5m4nC 5m4pC 1uylS 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 on special symmetry positions |
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-Components
#1: Protein | Mass: 28523.869 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Tissue: Melanoma / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Organ: Skin / Plasmid: PET19 / Production host: Escherichia coli BL21(DE3) / References: UniProt: P07900 |
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#2: Chemical | ChemComp-7F9 / ~{ |
#3: Chemical | ChemComp-SO4 / |
#4: 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: 2.54 Å3/Da / Density % sol: 51.56 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion / pH: 6.5 Details: 0.1 M Na Cacodylate pH 6.5 25% PEG 2K MME 0.2 M MgCl2 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5412 Å |
Detector | Type: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 1, 2009 / Details: OSMIC BLUE MIRRORS |
Radiation | Monochromator: CU FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.5412 Å / Relative weight: 1 |
Reflection | Resolution: 1.9→24.64 Å / Num. obs: 22925 / % possible obs: 98.5 % / Redundancy: 2.7 % / Rmerge(I) obs: 0.062 / Net I/σ(I): 9.9 |
Reflection shell | Resolution: 1.9→1.97 Å / Redundancy: 2.43 % / Rmerge(I) obs: 0.259 / Mean I/σ(I) obs: 3.3 / % possible all: 94.9 |
-Processing
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1UYL Resolution: 1.9→24.64 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.943 / SU B: 2.868 / SU ML: 0.083 / Cross valid method: THROUGHOUT / ESU R: 0.118 / ESU R Free: 0.126 / 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: 1.2 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 26.981 Å2
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Refinement step | Cycle: 1 / Resolution: 1.9→24.64 Å
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Refine LS restraints |
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