+Open data
-Basic information
Entry | Database: PDB / ID: 6zba | ||||||
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Title | Crystal structure of PDE4D2 in complex with inhibitor LEO39652 | ||||||
Components | cAMP-specific 3',5'-cyclic phosphodiesterase 4D | ||||||
Keywords | HYDROLASE / phosphodiesterase / phosphodiesterase inhibitor | ||||||
Function / homology | Function and homology information signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / regulation of cardiac muscle cell contraction / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / regulation of cardiac muscle cell contraction / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of heart rate / heterocyclic compound binding / adrenergic receptor signaling pathway / voltage-gated calcium channel complex / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / calcium channel regulator activity / cAMP-mediated signaling / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / DARPP-32 events / negative regulation of peptidyl-serine phosphorylation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cAMP binding / cellular response to cAMP / cellular response to epinephrine stimulus / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / positive regulation of type II interferon production / ATPase binding / T cell receptor signaling pathway / G alpha (s) signalling events / scaffold protein binding / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / signal transduction / membrane / metal ion binding / nucleus / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å | ||||||
Authors | Akutsu, M. / Hakansson, M. / Welin, M. / Svensson, A. / Logan, D.T. / Sorensen, M.D. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2020 Title: Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H -isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a ]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual- ...Title: Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H -isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a ]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis. Authors: Larsen, J. / Lambert, M. / Pettersson, H. / Vifian, T. / Larsen, M. / Ollerstam, A. / Hegardt, P. / Eskilsson, C. / Laursen, S. / Soehoel, A. / Skak-Nielsen, T. / Hansen, L.M. / Knudsen, N.O. ...Authors: Larsen, J. / Lambert, M. / Pettersson, H. / Vifian, T. / Larsen, M. / Ollerstam, A. / Hegardt, P. / Eskilsson, C. / Laursen, S. / Soehoel, A. / Skak-Nielsen, T. / Hansen, L.M. / Knudsen, N.O. / Eirefelt, S. / Sorensen, M.D. / Stilou, T.G. / Nielsen, S.F. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6zba.cif.gz | 330.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6zba.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 6zba.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zb/6zba ftp://data.pdbj.org/pub/pdb/validation_reports/zb/6zba | HTTPS FTP |
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-Related structure data
Related structure data | 1y2kS 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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Unit cell |
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-Components
-Protein , 1 types, 4 molecules AAABBBCCCDDD
#1: Protein | Mass: 41368.758 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host: Escherichia coli (E. coli) References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase |
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-Non-polymers , 6 types, 1388 molecules
#2: Chemical | ChemComp-QDT / #3: Chemical | ChemComp-EDO / #4: Chemical | ChemComp-DMS / #5: Chemical | ChemComp-MG / #6: Chemical | ChemComp-ZN / #7: Water | ChemComp-HOH / | |
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-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: 2.7 Å3/Da / Density % sol: 54.42 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, sitting drop Details: Protein stored at 20.6 mg/mL in a storage buffer of 50 mM NaCl, 20 mM Tris HCl (pH 7.5), 1 mM TCEP, 1 mM EDTA. Reservoir was 0.1 M HEPES (pH 7.5), 19% PEG3350, 25% ethylene glycol, 5% 2- ...Details: Protein stored at 20.6 mg/mL in a storage buffer of 50 mM NaCl, 20 mM Tris HCl (pH 7.5), 1 mM TCEP, 1 mM EDTA. Reservoir was 0.1 M HEPES (pH 7.5), 19% PEG3350, 25% ethylene glycol, 5% 2-propanol, 5% glycerol. Drops were microseeded. Apo crystals were soaked with 0.8 mM LEO39652A for 3 days. |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å |
Detector | Type: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Sep 23, 2019 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9159 Å / Relative weight: 1 |
Reflection | Resolution: 1.6→79.939 Å / Num. obs: 235229 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.085 / Net I/σ(I): 9.2 |
Reflection shell | Resolution: 1.6→1.63 Å / Redundancy: 6 % / Rmerge(I) obs: 1.481 / Mean I/σ(I) obs: 1 / Num. unique obs: 11558 / CC1/2: 0.422 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1Y2K Resolution: 1.6→79.939 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.966 / SU B: 1.751 / SU ML: 0.057 / Cross valid method: THROUGHOUT / ESU R: 0.071 / ESU R Free: 0.074 Details: Hydrogens were added in their riding positions for refinement but removed for deposition.
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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: BABINET MODEL PLUS MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 27.135 Å2
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Refinement step | Cycle: LAST / Resolution: 1.6→79.939 Å
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Refine LS restraints |
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LS refinement shell |
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