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Yorodumi- PDB-6g92: Fragment-based discovery of a highly potent, orally bioavailable ... -
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-Basic information
Entry | Database: PDB / ID: 6g92 | ||||||
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Title | Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2 | ||||||
Components | Mitogen-activated protein kinase 1 | ||||||
Keywords | SIGNALING PROTEIN / Erk2 Kinase inhibitor | ||||||
Function / homology | Function and homology information phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated ...phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / regulation of cellular pH / positive regulation of macrophage proliferation / outer ear morphogenesis / Regulation of the apoptosome activity / regulation of Golgi inheritance / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of cytoskeleton organization / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / response to exogenous dsRNA / lung morphogenesis / ERBB2-ERBB3 signaling pathway / face development / Recycling pathway of L1 / Activation of the AP-1 family of transcription factors / androgen receptor signaling pathway / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / pseudopodium / progesterone receptor signaling pathway / positive regulation of telomere capping / MAPK1 (ERK2) activation / negative regulation of cell differentiation / Bergmann glial cell differentiation / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone mediated signaling pathway / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / regulation of ossification / MAP kinase activity / phosphatase binding / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / stress-activated MAPK cascade / Schwann cell development / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / ERK1 and ERK2 cascade / cellular response to cadmium ion / positive regulation of telomere maintenance via telomerase / cellular response to amino acid starvation / myelination / NPAS4 regulates expression of target genes / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / RNA polymerase II CTD heptapeptide repeat kinase activity / ESR-mediated signaling / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / response to nicotine / Regulation of PTEN gene transcription / Signal transduction by L1 / long-term synaptic potentiation / caveola / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / Spry regulation of FGF signaling / peptidyl-threonine phosphorylation / Signaling by high-kinase activity BRAF mutants / regulation of protein stability / MAP2K and MAPK activation / Oncogene Induced Senescence / mitotic spindle / Regulation of actin dynamics for phagocytic cup formation Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.99 Å | ||||||
Authors | O'Reilly, M. | ||||||
Citation | Journal: J. Med. Chem. / Year: 2018 Title: Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2. Authors: Heightman, T.D. / Berdini, V. / Braithwaite, H. / Buck, I.M. / Cassidy, M. / Castro, J. / Courtin, A. / Day, J.E.H. / East, C. / Fazal, L. / Graham, B. / Griffiths-Jones, C.M. / Lyons, J.F. ...Authors: Heightman, T.D. / Berdini, V. / Braithwaite, H. / Buck, I.M. / Cassidy, M. / Castro, J. / Courtin, A. / Day, J.E.H. / East, C. / Fazal, L. / Graham, B. / Griffiths-Jones, C.M. / Lyons, J.F. / Martins, V. / Muench, S. / Munck, J.M. / Norton, D. / O'Reilly, M. / Palmer, N. / Pathuri, P. / Reader, M. / Rees, D.C. / Rich, S.J. / Richardson, C. / Saini, H. / Thompson, N.T. / Wallis, N.G. / Walton, H. / Wilsher, N.E. / Woolford, A.J. / Cooke, M. / Cousin, D. / Onions, S. / Shannon, J. / Watts, J. / Murray, C.W. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6g92.cif.gz | 165.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6g92.ent.gz | 133.3 KB | Display | PDB format |
PDBx/mmJSON format | 6g92.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/g9/6g92 ftp://data.pdbj.org/pub/pdb/validation_reports/g9/6g92 | HTTPS FTP |
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-Related structure data
Related structure data | 6g8xC 6g91C 6g93C 6g97C 6g9aC 6g9dC 6g9hC 6g9jC 6g9kC 6g9mC 6g9nC 6gdmC 6gdqC 6ge0C 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: 42551.922 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Production host: Escherichia coli BL21 (bacteria) References: UniProt: P28482, mitogen-activated protein kinase | ||||
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#2: Chemical | #3: Chemical | ChemComp-ERZ / ~{ | #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: 2.32 Å3/Da / Density % sol: 46.91 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2 Details: 0.2M (NH4)2SO4, 0.1M HEPES/NaOHpH=7.2, 34.0%w/v MPEG 2000, 0.02M Mercaptoethanol |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å |
Detector | Type: RIGAKU SATURN 944 / Detector: CCD / Date: Nov 13, 2014 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.54178 Å / Relative weight: 1 |
Reflection | Resolution: 1.99→46.14 Å / Num. obs: 26685 / % possible obs: 99.4 % / Redundancy: 3.3 % / Biso Wilson estimate: 23.59 Å2 / Rrim(I) all: 0.153 / Net I/σ(I): 5.8 |
Reflection shell | Resolution: 1.99→2.03 Å / Rmerge(I) obs: 0.85 / Num. unique obs: 561 / % possible all: 95.5 |
-Processing
Software |
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Refinement | Method to determine structure: FOURIER SYNTHESIS / Resolution: 1.99→30.12 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.916 / SU R Cruickshank DPI: 0.434 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.192 / SU Rfree Blow DPI: 0.17 / SU Rfree Cruickshank DPI: 0.16
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Displacement parameters | Biso mean: 33.173 Å2
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Refine analyze | Luzzati coordinate error obs: 0.2 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: 1 / Resolution: 1.99→30.12 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.99→2.07 Å / Total num. of bins used: 13
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Refinement TLS params. | Method: refined / Origin x: -0.7498 Å / Origin y: 3.6625 Å / Origin z: 38.0872 Å
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Refinement TLS group | Selection details: { A|8 - A|365 } |