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- PDB-7f2k: Crystal structure of PDE4D catalytic domain complexed with compou... -

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Basic information

Entry
Database: PDB / ID: 7f2k
TitleCrystal structure of PDE4D catalytic domain complexed with compound 17a
ComponentsIsoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4 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 / 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-0X8 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.10001966681 Å
AuthorsHuang, Y.-Y. / He, X. / Luo, H.-B.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21877134 China
National Natural Science Foundation of China (NSFC)22077143 China
National Natural Science Foundation of China (NSFC)82003576 China
CitationJournal: J.Med.Chem. / Year: 2021
Title: Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety.
Authors: Huang, Y.Y. / Deng, J. / Tian, Y.J. / Liang, J. / Xie, X. / Huang, Y. / Zhu, J. / Zhu, Z. / Zhou, Q. / He, X. / Luo, H.B.
History
DepositionJun 11, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 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

Downloads & links

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Assembly

Deposited unit
A: Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D
B: Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,8838
Polymers115,7192
Non-polymers1,1646
Water5,188288
1
A: Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,4424
Polymers57,8601
Non-polymers5823
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area80 Å2
ΔGint-34 kcal/mol
Surface area14660 Å2
MethodPISA
2
B: Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,4424
Polymers57,8601
Non-polymers5823
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area80 Å2
ΔGint-33 kcal/mol
Surface area14370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.063, 80.697, 163.385
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 Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D / DPDE3 / PDE43


Mass: 57859.504 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-0X8 / (~{E})-4-[8-methoxy-2,2-dimethyl-7-(3-methylbut-2-enyl)-9-oxidanyl-6-oxidanylidene-pyrano[3,2-b]xanthen-5-yl]oxybut-2-enoic acid


Mass: 492.517 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H28O8 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 288 / 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: 1.65 Å3/Da / Density % sol: 25.63 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.1 M HEPES (pH 7.4), 0.1 M MgCl2, 15% PEG3350, 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: Mar 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→23.58 Å / Num. obs: 45574 / % possible obs: 99.8 % / Redundancy: 4.3 % / Biso Wilson estimate: 21.3256254028 Å2 / Rmerge(I) obs: 0.075 / Net I/σ(I): 15.3
Reflection shellResolution: 2.1→2.2 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.311 / Mean I/σ(I) obs: 2.8 / Num. unique obs: 4490 / % possible all: 99.6

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQA

5wqa


Resolution: 2.10001966681→23.5783341262 Å / SU ML: 0.253969836619 / Cross valid method: NONE / σ(F): 1.35988904769 / Phase error: 24.0687303043
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.256955453423 2235 4.90443483795 %
Rwork0.208256947539 43336 -
obs0.210622474087 45571 99.8225707527 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.2593589744 Å2
Refinement stepCycle: LAST / Resolution: 2.10001966681→23.5783341262 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5174 0 76 288 5538
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008264332424655359
X-RAY DIFFRACTIONf_angle_d0.9518337896317291
X-RAY DIFFRACTIONf_chiral_restr0.047537729376828
X-RAY DIFFRACTIONf_plane_restr0.00625609663244989
X-RAY DIFFRACTIONf_dihedral_angle_d20.95159824162001
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1001-2.14570.3232360832961350.2893011156222686X-RAY DIFFRACTION99.5764207554
2.1457-2.19550.3130263293321520.25973374692625X-RAY DIFFRACTION99.5697382574
2.1955-2.25040.3148660616811340.2589542748772696X-RAY DIFFRACTION99.61281239
2.2504-2.31120.3277041633711290.2542897590542660X-RAY DIFFRACTION99.6427295463
2.3112-2.37910.3282249417121320.2476096176862655X-RAY DIFFRACTION99.4291830182
2.3791-2.45580.2678001925151240.2284094227112682X-RAY DIFFRACTION99.6802841918
2.4558-2.54350.3074343787541340.2309547637132697X-RAY DIFFRACTION99.9646892655
2.5435-2.64520.2668952269991360.2249846900062687X-RAY DIFFRACTION100
2.6452-2.76540.2681626120981530.2112552581382710X-RAY DIFFRACTION100
2.7654-2.9110.2642786332251320.2169680709332686X-RAY DIFFRACTION100
2.911-3.0930.2976262268841340.2138706975442707X-RAY DIFFRACTION100
3.093-3.33120.2331045660991520.209661797542698X-RAY DIFFRACTION100
3.3312-3.66530.2208308127691440.1933753129162728X-RAY DIFFRACTION99.8956521739
3.6653-4.19310.234905555491550.1768420792322734X-RAY DIFFRACTION100
4.1931-5.27320.2091516525521430.1646023909182787X-RAY DIFFRACTION99.931787176
5.2732-23.5780.2160204784681460.1827717098182898X-RAY DIFFRACTION99.8360118071

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