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Yorodumi- PDB-6xih: Structure-guided optimization of a novel class of ASK1 inhibitors... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6xih | ||||||
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Title | Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile | ||||||
Components | Mitogen-activated protein kinase kinase kinase 5 | ||||||
Keywords | METAL BINDING PROTEIN / TRANSFERASE / METAL-BINDING / APOPTOSIS / Serine/threonine kinase | ||||||
Function / homology | Function and homology information cellular response to reactive nitrogen species / neuron intrinsic apoptotic signaling pathway in response to oxidative stress / IRE1-TRAF2-ASK1 complex / protein kinase complex / mitogen-activated protein kinase kinase kinase / programmed necrotic cell death / JUN kinase kinase kinase activity / endothelial cell apoptotic process / MAP kinase kinase kinase activity / positive regulation of p38MAPK cascade ...cellular response to reactive nitrogen species / neuron intrinsic apoptotic signaling pathway in response to oxidative stress / IRE1-TRAF2-ASK1 complex / protein kinase complex / mitogen-activated protein kinase kinase kinase / programmed necrotic cell death / JUN kinase kinase kinase activity / endothelial cell apoptotic process / MAP kinase kinase kinase activity / positive regulation of p38MAPK cascade / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of cardiac muscle cell apoptotic process / p38MAPK cascade / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of protein kinase activity / positive regulation of myoblast differentiation / stress-activated MAPK cascade / JNK cascade / positive regulation of JUN kinase activity / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to amino acid starvation / response to endoplasmic reticulum stress / response to ischemia / apoptotic signaling pathway / positive regulation of JNK cascade / cellular senescence / cellular response to hydrogen peroxide / MAPK cascade / cellular response to tumor necrosis factor / protein phosphatase binding / Oxidative Stress Induced Senescence / neuron apoptotic process / protein kinase activity / protein domain specific binding / positive regulation of apoptotic process / protein phosphorylation / external side of plasma membrane / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / positive regulation of DNA-templated transcription / protein kinase binding / magnesium ion binding / protein homodimerization activity / protein-containing complex / ATP binding / identical protein binding / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å | ||||||
Authors | Dougan, D.R. | ||||||
Citation | Journal: Bioorg.Med.Chem.Lett. / Year: 2020 Title: Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3character and an exquisite selectivity profile. Authors: Bigi-Botterill, S.V. / Ivetac, A. / Bradshaw, E.L. / Cole, D. / Dougan, D.R. / Ermolieff, J. / Halkowycz, P. / Johnson, B. / McBride, C. / Pickens, J. / Sabat, M. / Swann, S. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6xih.cif.gz | 220.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6xih.ent.gz | 176.8 KB | Display | PDB format |
PDBx/mmJSON format | 6xih.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6xih_validation.pdf.gz | 998.4 KB | Display | wwPDB validaton report |
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Full document | 6xih_full_validation.pdf.gz | 1004.1 KB | Display | |
Data in XML | 6xih_validation.xml.gz | 20.3 KB | Display | |
Data in CIF | 6xih_validation.cif.gz | 27.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xi/6xih ftp://data.pdbj.org/pub/pdb/validation_reports/xi/6xih | HTTPS FTP |
-Related structure data
Related structure data | 5usqS S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 33306.035 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K5, ASK1, MAPKKK5, MEKK5 / Plasmid: pEH8 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2(DE3) pLysS References: UniProt: Q99683, mitogen-activated protein kinase kinase kinase #2: Chemical | #3: Water | ChemComp-HOH / | 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: 2.9 Å3/Da / Density % sol: 57.57 % / Mosaicity: 0.35 ° |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6 Details: 6% polyethylene glycol 2000 MME , 20% glycerol, 0.1M MES, pH 6.0 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 22, 2014 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.976 Å / Relative weight: 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 2.63→50 Å / Num. obs: 24937 / % possible obs: 99.9 % / Redundancy: 10.5 % / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.041 / Rrim(I) all: 0.115 / Χ2: 1.052 / Net I/σ(I): 6.4 / Num. measured all: 261550 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 5USQ Resolution: 2.65→30 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.896 / SU B: 30.663 / SU ML: 0.289 / SU R Cruickshank DPI: 0.511 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.511 / ESU R Free: 0.343 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
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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 max: 197.22 Å2 / Biso mean: 77.64 Å2 / Biso min: 31.49 Å2
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Refinement step | Cycle: final / Resolution: 2.65→30 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.65→2.718 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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