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- PDB-7w4x: Crystal structure of PDE4D catalytic domain complexed with 17 -

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Basic information

Entry
Database: PDB / ID: 7w4x
TitleCrystal structure of PDE4D catalytic domain complexed with 17
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / cAMP-specific 3' / 5'-cyclic phosphodiesterase 4D
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) / 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-8G7 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.20007326465 Å
AuthorsHuang, Y.-Y. / Luo, H.-B.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)22077144 China
National Natural Science Foundation of China (NSFC)82003576 China
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis.
Authors: Song, Z. / Huang, Y.Y. / Hou, K.Q. / Liu, L. / Zhou, F. / Huang, Y. / Wan, G. / Luo, H.B. / Xiong, X.F.
History
DepositionNov 29, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)86,4148
Polymers85,5782
Non-polymers8366
Water4,720262
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2074
Polymers42,7891
Non-polymers4183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-33 kcal/mol
Surface area14830 Å2
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2074
Polymers42,7891
Non-polymers4183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area80 Å2
ΔGint-33 kcal/mol
Surface area14980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.810, 80.301, 163.288
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 42789.055 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 (bacteria)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase
#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.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-8G7 / (2R,4S)-2-(2-hydroxyethyl)-2,6-dimethyl-4-(2-methylprop-1-enyl)-3,4-dihydropyrano[3,2-c][1,8]naphthyridin-5-one


Mass: 328.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H24N2O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 262 / Source method: isolated from a natural source / Formula: H2O
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: 2.21 Å3/Da / Density % sol: 44.45 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 0.1 M Hepes (pH 7.4), 0.1 M MgCl2, 15% PEG 3350, 10% isopropanol, and 25% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU HyPix-3000 / Detector: PIXEL / Date: Jan 2, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→22.634 Å / Num. obs: 39230 / % possible obs: 99.47 % / Redundancy: 3.6 % / Biso Wilson estimate: 25.8727032441 Å2 / Rmerge(I) obs: 0.051 / Net I/σ(I): 22.9
Reflection shellResolution: 2.2→2.3 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 4.2 / Num. unique obs: 3582 / % possible all: 99.64

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
CrysalisPro171.39.46data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5wqa
Resolution: 2.20007326465→22.6335957689 Å / SU ML: 0.232054808065 / Cross valid method: NONE / σ(F): 1.34950362119 / Phase error: 25.2295930099
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.252792779593 1881 4.79504435607 %
Rwork0.228741688885 37347 -
obs0.229920525619 39228 99.5912564422 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.9562702411 Å2
Refinement stepCycle: LAST / Resolution: 2.20007326465→22.6335957689 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5244 0 52 262 5558
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004160808632345404
X-RAY DIFFRACTIONf_angle_d0.5964093238187350
X-RAY DIFFRACTIONf_chiral_restr0.0413982011637842
X-RAY DIFFRACTIONf_plane_restr0.00538209848868976
X-RAY DIFFRACTIONf_dihedral_angle_d21.43554614122010
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2001-2.25950.2999578791851400.264407050682785X-RAY DIFFRACTION99.6253405995
2.2595-2.32590.2499330067341170.258456958912881X-RAY DIFFRACTION99.7006983705
2.3259-2.40090.287380434351500.2486821214192846X-RAY DIFFRACTION99.7668997669
2.4009-2.48660.2638175806721300.2479986346422833X-RAY DIFFRACTION99.7979117548
2.4866-2.58610.3111566968731400.2584251752732855X-RAY DIFFRACTION99.8666222074
2.5861-2.70360.260621317171660.2504861041162833X-RAY DIFFRACTION99.9666666667
2.7036-2.84590.2620146408011490.2418842630862873X-RAY DIFFRACTION99.9669202779
2.8459-3.02380.2489494021751490.239658857242854X-RAY DIFFRACTION99.8337765957
3.0238-3.25660.2545267354021300.237543568762869X-RAY DIFFRACTION99.7007978723
3.2566-3.58320.27333214531380.2271690606072902X-RAY DIFFRACTION99.9014130792
3.5832-4.0990.2242890888651590.2160097787922898X-RAY DIFFRACTION99.7064579256
4.099-5.15420.2323806036621460.2017102955732917X-RAY DIFFRACTION99.1262135922
5.1542-22.630.2391448305661670.2075371573913001X-RAY DIFFRACTION97.8986402967

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