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- PDB-8zqu: The crystal structure of PDE4D with isoaurostatin derivatives 2-6 -

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Basic information

Entry
Database: PDB / ID: 8zqu
TitleThe crystal structure of PDE4D with isoaurostatin derivatives 2-6
Components3',5'-cyclic-AMP phosphodiesterase 4D
KeywordsHYDROLASE / Inhibitor
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 / 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 relaxation of cardiac muscle / negative regulation of heart contraction / 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 / calcium channel complex / positive regulation of interleukin-2 production / cellular response to epinephrine stimulus / 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
: / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.00004554556 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)116,4738
Polymers115,5172
Non-polymers9566
Water4,882271
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1960 Å2
ΔGint-105 kcal/mol
Surface area27660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.475, 80.619, 163.765
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-A1D8P / (3~{Z})-3-[[4-[bis(fluoranyl)methoxy]-3-cyclopentyloxy-phenyl]methylidene]-6-oxidanyl-1-benzofuran-2-one


Mass: 388.361 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18F2O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 271 / 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: 1.67 Å3/Da / Density % sol: 26.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting 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: Mar 18, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→23.6449 Å / Num. obs: 53059 / % possible obs: 99.7 % / Redundancy: 4.4 % / Biso Wilson estimate: 20.0423603012 Å2 / Rmerge(I) obs: 0.061 / Net I/σ(I): 13.8
Reflection shellResolution: 2→2.1 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 3827 / % possible all: 99.1

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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: 2.00004554556→23.6448946434 Å / SU ML: 0.241215608104 / Cross valid method: NONE / σ(F): 1.35152087284 / Phase error: 24.2478002829
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.242599170545 2669 5.03575404238 %
Rwork0.206263307542 50332 -
obs0.208116912168 53001 99.7234138632 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.1806979271 Å2
Refinement stepCycle: LAST / Resolution: 2.00004554556→23.6448946434 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5221 0 60 271 5552
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007615926952365389
X-RAY DIFFRACTIONf_angle_d0.887153454027324
X-RAY DIFFRACTIONf_chiral_restr0.0473603350084837
X-RAY DIFFRACTIONf_plane_restr0.00529306251057956
X-RAY DIFFRACTIONf_dihedral_angle_d15.00196585523270
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.00005-2.03640.3282794543411300.282380551992583X-RAY DIFFRACTION98.6545454545
2.0364-2.07550.2830147505161260.2400326912362642X-RAY DIFFRACTION99.4252873563
2.0755-2.11790.247898931671240.2436512232472603X-RAY DIFFRACTION99.4529540481
2.1179-2.16390.3009351849491400.2357864958732627X-RAY DIFFRACTION99.5323741007
2.1639-2.21420.2917913154661300.2300393325062596X-RAY DIFFRACTION99.7438712038
2.2142-2.26950.2778173048381360.22244586942602X-RAY DIFFRACTION99.8905508938
2.2695-2.33080.3189672982821450.2192958640092647X-RAY DIFFRACTION99.9641962048
2.3308-2.39940.2799139493911410.2141504177882600X-RAY DIFFRACTION99.8906705539
2.3994-2.47670.2339395404021350.2121136484912635X-RAY DIFFRACTION99.9639119451
2.4767-2.56510.2854106791021580.2134919820942632X-RAY DIFFRACTION99.9641705482
2.5651-2.66770.2569531798041480.2152183336792626X-RAY DIFFRACTION100
2.6677-2.7890.2741293998931340.2130790085772671X-RAY DIFFRACTION100
2.789-2.93570.2367024950141400.2140295339342639X-RAY DIFFRACTION99.964028777
2.9357-3.11930.2701761888261390.2191864962282660X-RAY DIFFRACTION99.9642857143
3.1193-3.35950.295133893871430.2138003528612670X-RAY DIFFRACTION100
3.3595-3.69640.2295134998031370.2050142354832688X-RAY DIFFRACTION100
3.6964-4.22870.2151048847111490.1826565353252679X-RAY DIFFRACTION100
4.2287-5.31770.1594619708841600.1674884070512723X-RAY DIFFRACTION99.896049896
5.3177-23.64480.1866520849611540.1754228033982809X-RAY DIFFRACTION98.667998668

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