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

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Basic information

Entry
Database: PDB / ID: 6fdc
TitleCrystal structure of the PDE4D catalytic domain in complex with GEBR-32a
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 / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of interleukin-5 production / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / heterocyclic compound binding / beta-2 adrenergic receptor binding ...signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of interleukin-5 production / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / heterocyclic compound binding / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / adrenergic receptor signaling pathway / cAMP catabolic process / regulation of cell communication by electrical coupling involved in cardiac conduction / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / DARPP-32 events / : / positive regulation of heart rate / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to epinephrine stimulus / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / cellular response to cAMP / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / calcium channel regulator activity / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / nuclear membrane / G alpha (s) signalling events / transmembrane transporter binding / cilium / apical plasma membrane / centrosome / enzyme binding / nucleoplasm / metal ion binding / membrane / 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-D5N / Chem-DD5 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 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 22, 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 1.2May 8, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_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.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.ptnr1_symmetry / _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)80,50113
Polymers79,2502
Non-polymers1,25111
Water9,080504
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 area2590 Å2
ΔGint-108 kcal/mol
Surface area28000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.692, 98.608, 120.165
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, 515 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.: 5 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-DD5 / (2~{R})-1-[3-[4-[bis(fluoranyl)methoxy]-3-cyclopentyloxy-phenyl]pyrazol-1-yl]-3-morpholin-4-yl-propan-2-ol


Mass: 437.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29F2N3O4
#6: Chemical ChemComp-D5N / (2~{S})-1-[5-[4-[bis(fluoranyl)methoxy]-3-cyclopentyloxy-phenyl]pyrazol-1-yl]-3-morpholin-4-yl-propan-2-ol


Mass: 437.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29F2N3O4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 504 / 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: 2.42 Å3/Da / Density % sol: 49.13 %
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 5, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.45→49.324 Å / Num. obs: 263295 / % possible obs: 100 % / Redundancy: 13.2 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 21.5
Reflection shellResolution: 1.45→1.763 Å

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
PHENIXphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.45→49.324 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.27 / Phase error: 19.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1993 13176 5 %
Rwork0.1782 --
obs0.1792 263295 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.45→49.324 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5265 0 77 504 5846
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065543
X-RAY DIFFRACTIONf_angle_d1.0387549
X-RAY DIFFRACTIONf_dihedral_angle_d14.0582074
X-RAY DIFFRACTIONf_chiral_restr0.065867
X-RAY DIFFRACTIONf_plane_restr0.005965
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.45-1.46650.29264340.26448378X-RAY DIFFRACTION100
1.4665-1.48370.2734360.25458266X-RAY DIFFRACTION100
1.4837-1.50180.24624420.24288375X-RAY DIFFRACTION100
1.5018-1.52080.23574420.23388347X-RAY DIFFRACTION100
1.5208-1.54090.22914430.22738332X-RAY DIFFRACTION100
1.5409-1.5620.23324390.21828290X-RAY DIFFRACTION100
1.562-1.58430.22584390.21428367X-RAY DIFFRACTION100
1.5843-1.60790.23794380.2088329X-RAY DIFFRACTION100
1.6079-1.63310.23034410.19678328X-RAY DIFFRACTION100
1.6331-1.65980.22064330.19998370X-RAY DIFFRACTION100
1.6598-1.68850.20484370.19698334X-RAY DIFFRACTION100
1.6885-1.71920.20294350.19118297X-RAY DIFFRACTION100
1.7192-1.75220.22724450.18928396X-RAY DIFFRACTION100
1.7522-1.7880.20224420.19368386X-RAY DIFFRACTION100
1.788-1.82690.23724320.18848267X-RAY DIFFRACTION100
1.8269-1.86940.19994450.19328378X-RAY DIFFRACTION100
1.8694-1.91610.22014370.18988288X-RAY DIFFRACTION100
1.9161-1.96790.21274470.18858357X-RAY DIFFRACTION100
1.9679-2.02580.20114390.18478345X-RAY DIFFRACTION100
2.0258-2.09120.20534380.18078314X-RAY DIFFRACTION100
2.0912-2.1660.18774410.17888318X-RAY DIFFRACTION100
2.166-2.25270.19094400.17248350X-RAY DIFFRACTION100
2.2527-2.35520.19044410.17358353X-RAY DIFFRACTION100
2.3552-2.47940.19154430.17838329X-RAY DIFFRACTION100
2.4794-2.63470.20614330.17488343X-RAY DIFFRACTION100
2.6347-2.83810.19414340.17768307X-RAY DIFFRACTION100
2.8381-3.12370.20474410.17868349X-RAY DIFFRACTION100
3.1237-3.57560.19684350.17158371X-RAY DIFFRACTION100
3.5756-4.50440.17234340.15058324X-RAY DIFFRACTION100
4.5044-49.35230.17694500.15458331X-RAY DIFFRACTION100

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