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- PDB-7b9h: Crystal structure of the PDE4D catalytic domain in complex with G... -

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Basic information

Entry
Database: PDB / ID: 7b9h
TitleCrystal structure of the PDE4D catalytic domain in complex with GEBR-42a
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / Phosphodiesterase 4D / Inhibitor / Complex / 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 / adrenergic receptor signaling pathway / heterocyclic compound binding / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / DARPP-32 events / 3',5'-cyclic-AMP phosphodiesterase activity / positive regulation of heart rate / cAMP-mediated signaling / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to cAMP / cellular response to epinephrine stimulus / calcium channel regulator activity / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / G alpha (s) signalling events / nuclear membrane / 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) / 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.
Similarity search - Domain/homology
Chem-T3K / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsTorretta, A. / Abbate, S. / Parisini, E.
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.
Authors: Brullo, C. / Rapetti, F. / Abbate, S. / Prosdocimi, T. / Torretta, A. / Semrau, M. / Massa, M. / Alfei, S. / Storici, P. / Parisini, E. / Bruno, O.
History
DepositionDec 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)82,09442
Polymers79,2502
Non-polymers2,84440
Water12,358686
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7520 Å2
ΔGint-48 kcal/mol
Surface area28820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.748, 98.628, 119.821
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 (E. coli)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 726 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.: 8 / Source method: obtained synthetically / Formula: Mg
#4: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 28 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-T3K / 3-[(~{E})-1-(3-cyclopentyloxy-4-methoxy-phenyl)ethylideneamino]oxy-1-morpholin-4-yl-propan-1-one


Mass: 390.473 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N2O5 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 686 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.41 Å3/Da / Density % sol: 49.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: PEG 3350, Magnesium Chloride, Hepes

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Nov 23, 2018 / Details: M
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→54.13 Å / Num. obs: 122986 / % possible obs: 99.8 % / Redundancy: 12.9 % / CC1/2: 0.999 / Net I/σ(I): 11.5
Reflection shellResolution: 1.5→1.53 Å / Num. unique obs: 5856 / CC1/2: 0.631

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Processing

Software
NameVersionClassification
PHENIX1.19rc7_4070refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PW3

2pw3


Resolution: 1.5→54.13 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 22.77 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2206 6199 5.05 %
Rwork0.1943 116439 -
obs0.1956 122638 99.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 102.52 Å2 / Biso mean: 27.9325 Å2 / Biso min: 10.67 Å2
Refinement stepCycle: final / Resolution: 1.5→54.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5333 0 182 689 6204
Biso mean--38.44 36.63 -
Num. residues----659
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5-1.520.38472540.36193688394297
1.52-1.530.43652040.43523761396598
1.53-1.550.29121740.28843828400299
1.55-1.570.30032180.26583823404199
1.57-1.590.25791990.24338294028100
1.59-1.620.27462200.233938874107100
1.62-1.640.24812160.222338184034100
1.64-1.660.25922240.229138684092100
1.66-1.690.26672130.214838164029100
1.69-1.720.27351940.231438784072100
1.72-1.750.25922190.244438694088100
1.75-1.780.25281860.231438544040100
1.78-1.810.26712060.217639044110100
1.81-1.850.22982070.21138874094100
1.85-1.890.25082050.228938664071100
1.89-1.930.38541890.34773791398097
1.93-1.980.25891890.219538784067100
1.98-2.040.23892010.200339024103100
2.04-2.10.27192030.231838614064100
2.1-2.160.19752000.194738884088100
2.16-2.240.22511810.19713898407999
2.24-2.330.26952130.21513829404299
2.33-2.440.21752030.178939084111100
2.44-2.560.17912320.178639134145100
2.56-2.730.19821960.176539334129100
2.73-2.940.18942360.179939094145100
2.94-3.230.23021920.174639674159100
3.23-3.70.19892180.166639594177100
3.7-4.660.16391800.147840544234100
4.66-54.130.17552270.164341734400100

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