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- PDB-7ab9: Crystal structure of human phosphodiesterase 4D2 catalytic domain... -

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Basic information

Entry
Database: PDB / ID: 7ab9
TitleCrystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-656
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / Phosphodiesterase / cAMP hydrolysis / alternative splicing
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-QWZ / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsSingh, A.K. / Blaazer, A.R. / Zara, L. / de Esch, I.J.P. / Leurs, R. / Brown, D.G.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Union (EU)602666European Union
CitationJournal: To be published
Title: hPDE4D2 structure with inhibitor NPD-656
Authors: Singh, A.K. / Brown, D.G.
History
DepositionSep 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / diffrn_source / pdbx_initial_refinement_model
Item: _diffrn_source.pdbx_synchrotron_site

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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
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,85149
Polymers167,2334
Non-polymers4,61845
Water8,827490
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,98314
Polymers41,8081
Non-polymers1,17513
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6739
Polymers41,8081
Non-polymers8658
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,91110
Polymers41,8081
Non-polymers1,1039
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,28416
Polymers41,8081
Non-polymers1,47515
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.168, 111.797, 160.261
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, 4 molecules ABCD

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


Mass: 41808.242 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: residues 381-740 / Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Plasmid: pET15b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): codon plus
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 6 types, 535 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 31 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-QWZ / 1-cycloheptyl-3-{4-methoxy-3-[2-(4-methoxyphenyl)ethoxy]phenyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazol-5-one / 2-cycloheptyl-5-[4-methoxy-3-[2-(4-methoxyphenyl)ethoxy]phenyl]-4,4-dimethyl-pyrazol-3-one


Mass: 464.596 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H36N2O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 490 / 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: 2.66 Å3/Da / Density % sol: 53.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 24% PEG 3350, 30% Ethylene glycol, 0.1 M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 28, 2016 / Details: CRL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.18→160.26 Å / Num. obs: 92602 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.99 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.032 / Rrim(I) all: 0.082 / Net I/σ(I): 15.9
Reflection shellResolution: 2.18→2.19 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.991 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 934 / CC1/2: 0.61 / Rpim(I) all: 0.412 / Rrim(I) all: 1.075 / % possible all: 97.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SL3

3sl3


Resolution: 2.19→91.69 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.945 / SU B: 5.585 / SU ML: 0.137 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.214 / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2229 4687 5.1 %RANDOM
Rwork0.1851 ---
obs0.187 87492 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 147.13 Å2 / Biso mean: 48.68 Å2 / Biso min: 23.78 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å2-0 Å2-0 Å2
2---1.05 Å20 Å2
3---1.13 Å2
Refinement stepCycle: final / Resolution: 2.19→91.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10535 0 298 490 11323
Biso mean--75.19 51.04 -
Num. residues----1302
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01311026
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710182
X-RAY DIFFRACTIONr_angle_refined_deg1.441.64414920
X-RAY DIFFRACTIONr_angle_other_deg1.3531.57623635
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.28751298
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.23923.605602
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.508151913
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5581552
X-RAY DIFFRACTIONr_chiral_restr0.0740.21436
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212025
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022147
LS refinement shellResolution: 2.19→2.247 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.296 303 -
Rwork0.271 6410 -
all-6713 -
obs--100 %

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