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- PDB-7ay6: Crystal structure of the PDE4D catalytic domain in complex with G... -

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Basic information

Entry
Database: PDB / ID: 7ay6
TitleCrystal structure of the PDE4D catalytic domain in complex with GEBR-41b
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 / 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) / 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-S8Q / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 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
DepositionNov 11, 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)81,25328
Polymers79,2502
Non-polymers2,00326
Water13,097727
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4820 Å2
ΔGint-84 kcal/mol
Surface area28800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.838, 98.660, 120.239
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, 753 molecules

#2: Chemical ChemComp-S8Q / 2-[(~{Z})-1-(3-cyclopentyloxy-4-methoxy-phenyl)ethylideneamino]oxy-1-[(2~{S},6~{S})-2,6-dimethylmorpholin-4-yl]ethanone


Mass: 404.500 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H32N2O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 727 / 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: 2.43 Å3/Da / Density % sol: 49.31 %
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: 1.66→64.84 Å / Num. obs: 89823 / % possible obs: 98.5 % / Redundancy: 5.7 % / CC1/2: 0.996 / Net I/σ(I): 9.1
Reflection shellResolution: 1.66→1.69 Å / Num. unique obs: 3984 / CC1/2: 0.6 / % possible all: 90.1

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PW3

2pw3


Resolution: 1.66→49.33 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.31 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2142 4517 5.04 %
Rwork0.1815 85076 -
obs0.1832 89593 98.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 96.21 Å2 / Biso mean: 25.6982 Å2 / Biso min: 6.9 Å2
Refinement stepCycle: final / Resolution: 1.66→49.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5333 0 124 729 6186
Biso mean--37.92 35.2 -
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 (%)
1.66-1.680.32591320.28152523265589
1.68-1.70.29771450.27172555270089
1.7-1.720.29231550.24712566272193
1.72-1.740.28671390.24482744288395
1.74-1.770.26211380.23112770290896
1.77-1.790.26091480.2232830297898
1.79-1.820.2561520.21552787293999
1.82-1.840.23781820.21812808299099
1.84-1.870.28591550.23532852300799
1.87-1.90.32241550.26482827298299
1.9-1.940.3651280.305128773005100
1.94-1.970.21641530.206128392992100
1.97-2.010.22461530.189128663019100
2.01-2.050.21411640.185828212985100
2.05-2.10.21241220.176528983020100
2.1-2.140.21451760.179528413017100
2.14-2.20.20781350.17752866300199
2.2-2.260.30361290.23022845297498
2.26-2.320.24661410.19712848298998
2.32-2.40.21451530.17072862301599
2.4-2.480.21911380.16832850298899
2.48-2.580.21271700.16482854302499
2.58-2.70.20891470.1682883303099
2.7-2.840.17341420.16882896303899
2.84-3.020.23421390.172629143053100
3.02-3.250.21361710.166529063077100
3.25-3.580.16321350.160129503085100
3.58-4.10.19591580.151629403098100
4.1-5.160.16651840.140629473131100
5.17-49.330.17281780.166431113289100

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