+Open data
-Basic information
Entry | Database: PDB / ID: 8aoa | |||||||||
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Title | Covalent and non-covalent inhibitor of ERK2 (two sites) | |||||||||
Components | Mitogen-activated protein kinase 1 | |||||||||
Keywords | SIGNALING PROTEIN / serine-threonine kinase / transcriptional repressor / cell cycle / ATP binding | |||||||||
Function / homology | Function and homology information phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process ...phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / Regulation of the apoptosome activity / outer ear morphogenesis / regulation of cellular pH / 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 early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / regulation of cytoskeleton organization / face development / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / progesterone receptor signaling pathway / androgen receptor signaling pathway / RUNX2 regulates osteoblast differentiation / pseudopodium / Recycling pathway of L1 / MAPK1 (ERK2) activation / Bergmann glial cell differentiation / negative regulation of cell differentiation / positive regulation of telomere capping / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone receptor signaling pathway / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate NADPH Oxidases / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / phosphatase binding / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / Schwann cell development / Growth hormone receptor signaling / stress-activated MAPK cascade / lipopolysaccharide-mediated signaling pathway / : / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / myelination / cellular response to amino acid starvation / 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 / Regulation of PTEN gene transcription / Signal transduction by L1 / caveola / long-term synaptic potentiation / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / peptidyl-threonine phosphorylation / B cell receptor signaling pathway / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / response to nicotine / MAP2K and MAPK activation / regulation of protein stability / 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: 1.62 Å | |||||||||
Authors | Cleasby, A. | |||||||||
Funding support | United Kingdom, 1items
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Citation | Journal: J.Med.Chem. / Year: 2022 Title: X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor. Authors: St Denis, J.D. / Chessari, G. / Cleasby, A. / Cons, B.D. / Cowan, S. / Dalton, S.E. / East, C. / Murray, C.W. / O'Reilly, M. / Peakman, T. / Rapti, M. / Stow, J.L. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8aoa.cif.gz | 164.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8aoa.ent.gz | 129.2 KB | Display | PDB format |
PDBx/mmJSON format | 8aoa.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8aoa_validation.pdf.gz | 752.7 KB | Display | wwPDB validaton report |
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Full document | 8aoa_full_validation.pdf.gz | 754.3 KB | Display | |
Data in XML | 8aoa_validation.xml.gz | 19.7 KB | Display | |
Data in CIF | 8aoa_validation.cif.gz | 31 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ao/8aoa ftp://data.pdbj.org/pub/pdb/validation_reports/ao/8aoa | HTTPS FTP |
-Related structure data
Related structure data | 8ao2C 8ao3C 8ao4C 8ao5C 8ao6C 8ao7C 8ao8C 8ao9C 8aobC 8aocC 8aodC 8aoeC 8aofC 8aogC 8aohC 8aoiC 8aojC C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
-Protein , 1 types, 1 molecules A
#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(DE3) (bacteria) References: UniProt: P28482, mitogen-activated protein kinase |
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-Non-polymers , 6 types, 480 molecules
#2: Chemical | ChemComp-SO4 / | ||||||||
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#3: Chemical | #4: Chemical | ChemComp-DMS / | #5: Chemical | ChemComp-N83 / ~{ | #6: Chemical | ChemComp-OZU / ~{ | #7: Water | ChemComp-HOH / | |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.29 Å3/Da / Density % sol: 46.29 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop Details: 0.25M (NH4)2SO4 33% MPEG 2000 0.02M Mercaptoethanol 0.1M pH=7.2 HEPES/NaOH |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å |
Detector | Type: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Dec 22, 2019 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.54178 Å / Relative weight: 1 |
Reflection | Resolution: 1.62→56.82 Å / Num. obs: 40918 / % possible obs: 89.5 % / Redundancy: 2.9 % / Rrim(I) all: 0.041 / Net I/σ(I): 20.5 |
Reflection shell | Resolution: 1.62→1.728 Å / Num. unique obs: 588 / Rrim(I) all: 0.994 |
-Processing
Software |
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Refinement | Method to determine structure: FOURIER SYNTHESIS / Resolution: 1.62→44.2 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.142 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.117 / SU Rfree Blow DPI: 0.119 / SU Rfree Cruickshank DPI: 0.114 Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT ...Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
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Displacement parameters | Biso max: 124.12 Å2 / Biso mean: 29.27 Å2 / Biso min: 8.38 Å2
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Refine analyze | Luzzati coordinate error obs: 0.21 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 1.62→44.2 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.62→1.67 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
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Refinement TLS params. | Method: refined / Origin x: -1.0048 Å / Origin y: 3.6195 Å / Origin z: 38.0262 Å
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Refinement TLS group | Selection details: { A|11 - A|356 } |