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- PDB-6iag: Crystal structure of human phosphodiesterase 4D2 catalytic domain... -

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Basic information

Entry
Database: PDB / ID: 6iag
TitleCrystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-637
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 relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / regulation of cardiac muscle cell contraction / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / regulation of cardiac muscle cell contraction / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of heart rate / heterocyclic compound binding / adrenergic receptor signaling pathway / voltage-gated calcium channel complex / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / calcium channel regulator activity / cAMP-mediated signaling / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / DARPP-32 events / negative regulation of peptidyl-serine phosphorylation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cAMP binding / cellular response to cAMP / cellular response to epinephrine stimulus / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / positive regulation of type II interferon production / ATPase binding / T cell receptor signaling pathway / G alpha (s) signalling events / scaffold protein binding / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / signal transduction / membrane / metal ion binding / nucleus / 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-E3Q / DI(HYDROXYETHYL)ETHER / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsSingh, A.K. / Brown, D.G.
Funding support1items
OrganizationGrant numberCountry
European Union602666
CitationJournal: To be published
Title: hPDE4D2 structure with inhibitor NPD-637
Authors: Singh, A.K. / Brown, D.G.
History
DepositionNov 26, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release

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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)172,73257
Polymers167,2334
Non-polymers5,49953
Water11,800655
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,96914
Polymers41,8081
Non-polymers1,16113
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,19812
Polymers41,8081
Non-polymers1,38911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,89710
Polymers41,8081
Non-polymers1,0899
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,66821
Polymers41,8081
Non-polymers1,86020
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.108, 110.311, 160.722
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, 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 , 7 types, 708 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 / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 35 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-E3Q / 1-cycloheptyl-3-{4-methoxy-3-[(2-methoxyphenyl)methoxy]phenyl}-4,4-dimethyl-4,5-dihydro- 1H-pyrazol-5-one


Mass: 450.570 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H34N2O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 655 / 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: 2.63 Å3/Da / Density % sol: 53.26 %
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: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 2→90.93 Å / Num. obs: 119392 / % possible obs: 100 % / Redundancy: 6.5 % / CC1/2: 0.996 / Rmerge(I) obs: 0.118 / Rpim(I) all: 0.05 / Rrim(I) all: 0.129 / Net I/σ(I): 8.5
Reflection shellResolution: 2→2.05 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.763 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 8718 / CC1/2: 0.564 / Rpim(I) all: 0.321 / Rrim(I) all: 0.829 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
DIALSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→84.5 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.934 / SU B: 5.023 / SU ML: 0.131 / Cross valid method: THROUGHOUT / ESU R: 0.172 / ESU R Free: 0.162 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24614 5902 5 %RANDOM
Rwork0.19994 ---
obs0.20227 111310 98.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 35.584 Å2
Baniso -1Baniso -2Baniso -3
1--0.6 Å2-0 Å2-0 Å2
2---0.23 Å20 Å2
3---0.83 Å2
Refinement stepCycle: 1 / Resolution: 2→84.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10515 0 354 655 11524
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01311116
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710245
X-RAY DIFFRACTIONr_angle_refined_deg1.6211.64414991
X-RAY DIFFRACTIONr_angle_other_deg1.3571.57623789
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.04451298
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.90123.611601
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.654151912
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0881552
X-RAY DIFFRACTIONr_chiral_restr0.1180.21444
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212011
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022141
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.7623.5225198
X-RAY DIFFRACTIONr_mcbond_other2.7613.5225197
X-RAY DIFFRACTIONr_mcangle_it3.8235.2726491
X-RAY DIFFRACTIONr_mcangle_other3.8225.2726492
X-RAY DIFFRACTIONr_scbond_it3.7064.0025918
X-RAY DIFFRACTIONr_scbond_other3.7064.0035919
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.4945.8368500
X-RAY DIFFRACTIONr_long_range_B_refined7.2542.69512911
X-RAY DIFFRACTIONr_long_range_B_other7.2542.712912
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.999→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 429 -
Rwork0.366 7815 -
obs--94.34 %

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