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- PDB-6f8x: Crystal structure of the PDE4D catalytic domain in complex with G... -

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Basic information

Entry
Database: PDB / ID: 6f8x
TitleCrystal structure of the PDE4D catalytic domain in complex with GEBR-26g
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4 / catalytic domain / inhibitor / GEBR
Function / homology
Function and homology information


signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / heterocyclic compound binding / positive regulation of heart rate / adrenergic receptor signaling pathway / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-serine phosphorylation / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / DARPP-32 events / 3',5'-cyclic-GMP phosphodiesterase activity / calcium channel regulator activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to cAMP / cAMP-mediated signaling / calcium channel complex / cellular response to epinephrine stimulus / positive regulation of interleukin-2 production / regulation of heart rate / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / G alpha (s) signalling events / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / membrane / nucleus / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. ...Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-D08 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsProsdocimi, T. / Donini, S. / Parisini, E.
CitationJournal: Biochemistry / Year: 2018
Title: Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.
Authors: Prosdocimi, T. / Mollica, L. / Donini, S. / Semrau, M.S. / Lucarelli, A.P. / Aiolfi, E. / Cavalli, A. / Storici, P. / Alfei, S. / Brullo, C. / Bruno, O. / Parisini, E.
History
DepositionDec 13, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1May 23, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,49313
Polymers79,2502
Non-polymers1,24311
Water8,197455
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: Dimer is already characterized and validated in the literature.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2660 Å2
ΔGint-102 kcal/mol
Surface area27690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.547, 119.820, 64.502
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein cAMP-specific 3',5'-cyclic phosphodiesterase 4D / DPDE3 / PDE43


Mass: 39624.945 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 6 types, 466 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-D08 / 2-[(5~{R})-3-(3-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-1,2-oxazol-5-yl]-~{N},~{N}-bis(2-hydroxyethyl)ethanamide


Mass: 406.473 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N2O6 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 455 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.4 Å3/Da / Density % sol: 48.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: Hepes PEG 3350 Magnesium Chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Aug 20, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→49.208 Å / Num. obs: 107507 / % possible obs: 100 % / Redundancy: 13 % / Rmerge(I) obs: 0.124 / Net I/σ(I): 13
Reflection shellResolution: 1.95→2.266 Å

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
PHENIXphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6F6U

6f6u


Resolution: 1.95→49.208 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 18.96
RfactorNum. reflection% reflection
Rfree0.2046 5400 5.02 %
Rwork0.1665 --
obs0.1684 107507 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.95→49.208 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5222 0 76 455 5753
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075472
X-RAY DIFFRACTIONf_angle_d0.9327442
X-RAY DIFFRACTIONf_dihedral_angle_d14.0372041
X-RAY DIFFRACTIONf_chiral_restr0.038854
X-RAY DIFFRACTIONf_plane_restr0.004950
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.97220.27631770.23883414X-RAY DIFFRACTION100
1.9722-1.99540.29561800.21683433X-RAY DIFFRACTION100
1.9954-2.01970.26261790.21323389X-RAY DIFFRACTION100
2.0197-2.04530.23221850.19923394X-RAY DIFFRACTION100
2.0453-2.07220.22831800.18863408X-RAY DIFFRACTION100
2.0722-2.10060.19951830.18223427X-RAY DIFFRACTION100
2.1006-2.13060.21851780.17383356X-RAY DIFFRACTION100
2.1306-2.16240.22751820.18033400X-RAY DIFFRACTION100
2.1624-2.19620.21841850.17253430X-RAY DIFFRACTION100
2.1962-2.23220.1921800.16833399X-RAY DIFFRACTION100
2.2322-2.27070.21581740.16523389X-RAY DIFFRACTION100
2.2707-2.3120.22011820.15763421X-RAY DIFFRACTION100
2.312-2.35640.2011790.15523403X-RAY DIFFRACTION100
2.3564-2.40450.19331820.1563432X-RAY DIFFRACTION100
2.4045-2.45680.22591820.16123379X-RAY DIFFRACTION100
2.4568-2.51390.21831760.1653405X-RAY DIFFRACTION100
2.5139-2.57680.21841810.15873422X-RAY DIFFRACTION100
2.5768-2.64650.20781800.16583377X-RAY DIFFRACTION100
2.6465-2.72430.1811830.16813425X-RAY DIFFRACTION100
2.7243-2.81230.21711840.16393416X-RAY DIFFRACTION100
2.8123-2.91280.2411740.16973361X-RAY DIFFRACTION100
2.9128-3.02940.22131780.17733399X-RAY DIFFRACTION100
3.0294-3.16720.20031820.16893412X-RAY DIFFRACTION100
3.1672-3.33420.19771800.16213395X-RAY DIFFRACTION100
3.3342-3.5430.1851810.16453409X-RAY DIFFRACTION100
3.543-3.81650.18491830.15783412X-RAY DIFFRACTION100
3.8165-4.20040.17011820.14933396X-RAY DIFFRACTION100
4.2004-4.80770.18921740.14863396X-RAY DIFFRACTION100
4.8077-6.05550.17491820.17433392X-RAY DIFFRACTION100
6.0555-49.22370.21261720.15773416X-RAY DIFFRACTION100

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