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- PDB-8zqw: The crystal structure of PDE4D with isoaurostatin derivatives 2-9 -

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Basic information

Entry
Database: PDB / ID: 8zqw
TitleThe crystal structure of PDE4D with isoaurostatin derivatives 2-9
Components3',5'-cyclic-AMP phosphodiesterase 4D
KeywordsHYDROLASE / Inhibitor
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
: / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.10001903775 Å
AuthorsHuang, Y.-Y. / Luo, H.-B.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)22277019 China
CitationJournal: Chin.Chem.Lett. / Year: 2024
Title: Structure-based optimization of isoaurostatin as novel PDE4 inhibitors with anti-fibrotic effects
Authors: Huang, Y.Y. / Luo, X. / Zhang, K. / Liang, Y. / Zhang, F. / Liao, G. / Xie, S. / Huang, P.L. / Hou, S. / Zhou, Q. / Zou, Y. / Luo, H.B.
History
DepositionJun 3, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3',5'-cyclic-AMP phosphodiesterase 4D
B: 3',5'-cyclic-AMP phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,4718
Polymers115,5172
Non-polymers9546
Water3,081171
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1930 Å2
ΔGint-104 kcal/mol
Surface area27470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.767, 80.220, 162.931
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 3',5'-cyclic-AMP phosphodiesterase 4D / DPDE3 / PDE43 / cAMP-specific phosphodiesterase 4D


Mass: 57758.402 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-A1D8Q / (3~{Z})-3-[[4-[bis(fluoranyl)methoxy]-3-cyclopentyloxy-phenyl]methylidene]-6-oxidanyl-1~{H}-indol-2-one


Mass: 387.377 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H19F2NO4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 1.63 Å3/Da / Density % sol: 24.73 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1M HEPES (pH 7.4), 0.1M MgCl2, 15% PEG3350, 10% isopropanol, 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: Dec 17, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→23.4975 Å / Num. obs: 44865 / % possible obs: 99.6 % / Redundancy: 4.5 % / Biso Wilson estimate: 21.3104556492 Å2 / Rmerge(I) obs: 0.074 / Net I/av σ(I): 16.2 / Net I/σ(I): 16.2
Reflection shellResolution: 2.1→2.2 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.271 / Mean I/σ(I) obs: 3.4 / Num. unique obs: 4404 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMACV8refinement
PHENIX1.10_2155refinement
CrysalisPro171.39.46data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQA

5wqa


Resolution: 2.10001903775→23.4974071871 Å / SU ML: 0.251093288554 / Cross valid method: NONE / σ(F): 1.38459695052 / Phase error: 24.3230962043
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.255082992597 2245 5.00412366538 %
Rwork0.217392227749 42618 -
obs0.219310861706 44863 99.664548807 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.1190978754 Å2
Refinement stepCycle: LAST / Resolution: 2.10001903775→23.4974071871 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5208 0 60 171 5439
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003892415401735378
X-RAY DIFFRACTIONf_angle_d0.6801913720127312
X-RAY DIFFRACTIONf_chiral_restr0.0387834654414836
X-RAY DIFFRACTIONf_plane_restr0.00571580321804956
X-RAY DIFFRACTIONf_dihedral_angle_d16.34656400513264
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.10002-2.14570.282074092321320.2562339925922644X-RAY DIFFRACTION100
2.1457-2.19550.2822011032331410.2438734015372615X-RAY DIFFRACTION100
2.1955-2.25040.2908207867241500.2500971601912621X-RAY DIFFRACTION100
2.2504-2.31120.3152917283141260.2407799266242660X-RAY DIFFRACTION100
2.3112-2.37910.317098402061460.2391176886482621X-RAY DIFFRACTION100
2.3791-2.45580.267173095531430.2377319226332613X-RAY DIFFRACTION100
2.4558-2.54350.260664297241470.2370242596892658X-RAY DIFFRACTION100
2.5435-2.64520.2977045790731440.2355107431232651X-RAY DIFFRACTION100
2.6452-2.76540.2867116712941440.2318717580882659X-RAY DIFFRACTION100
2.7654-2.9110.3291584836451510.2317523964362641X-RAY DIFFRACTION99.9284180387
2.911-3.0930.2592623400661330.227455841172685X-RAY DIFFRACTION99.8582565556
3.093-3.33120.2790747664481210.2253509895612666X-RAY DIFFRACTION99.8209169054
3.3312-3.66530.2390247772361250.2171182197872700X-RAY DIFFRACTION99.4718309859
3.6653-4.19310.2224325965771450.2004512781022692X-RAY DIFFRACTION99.6837666901
4.1931-5.2730.2136365285091640.179384520662699X-RAY DIFFRACTION99.203049203
5.273-23.49740.1886993295811330.18294057942793X-RAY DIFFRACTION96.9195097714

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