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- PDB-6lrm: Crystal structure of PDE4D catalytic domain in complex with arctigenin -

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Basic information

Entry
Database: PDB / ID: 6lrm
TitleCrystal structure of PDE4D catalytic domain in complex with arctigenin
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4D / inhibitor / complex structure
Function / homology
Function and homology information


signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / 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 / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / beta-2 adrenergic receptor binding / voltage-gated calcium channel complex / positive regulation of heart rate / heterocyclic compound binding / adrenergic receptor signaling pathway / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / calcium channel regulator activity / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP 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 / cAMP-mediated signaling / calcium channel complex / cellular response to epinephrine stimulus / positive regulation of interleukin-2 production / regulation of heart rate / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / G alpha (s) signalling events / scaffold protein binding / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / 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
Arctigenin / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.45 Å
AuthorsZhang, X.L. / Li, M.J. / Xu, Y.C.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81620108027 China
National Natural Science Foundation of China (NSFC)21632008 China
CitationJournal: J Adv Res / Year: 2021
Title: Identification of phosphodiesterase-4 as the therapeutic target of arctigenin in alleviating psoriatic skin inflammation.
Authors: Li, H. / Zhang, X. / Xiang, C. / Feng, C. / Fan, C. / Liu, M. / Lu, H. / Su, H. / Zhou, Y. / Qi, Q. / Xu, Y. / Tang, W.
History
DepositionJan 16, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
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

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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,73134
Polymers80,1932
Non-polymers2,53832
Water6,467359
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7540 Å2
ΔGint-16 kcal/mol
Surface area26440 Å2
Unit cell
Length a, b, c (Å)57.879, 80.448, 163.733
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein cAMP-specific 3',5'-cyclic phosphodiesterase 4D / PDE4D / DPDE3 / PDE43


Mass: 40096.355 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(DE3) (bacteria)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 391 molecules

#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-EQC / Arctigenin / (3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-3-[(3-methoxy-4-oxidanyl-phenyl)methyl]oxolan-2-one / Arctigenin


Mass: 372.412 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24O6 / Feature type: SUBJECT OF INVESTIGATION / Comment: anticancer, antivirus*YM
#5: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 26 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 359 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.38 Å3/Da / Density % sol: 48.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M HEPES, pH 7.0, 0.2 M MgCl2, 10% isopropanol, 30% EG, 18% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.45→50 Å / Num. obs: 135892 / % possible obs: 99.9 % / Redundancy: 13.2 % / Biso Wilson estimate: 12.32 Å2 / Rmerge(I) obs: 0.044 / Rpim(I) all: 0.013 / Rrim(I) all: 0.046 / Χ2: 0.961 / Net I/σ(I): 16.9 / Num. measured all: 1788558
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.45-1.4812.70.67966700.9320.1980.7080.85299.8
1.48-1.513.30.54567250.9540.1550.5670.865100
1.5-1.5313.50.45467660.9690.1280.4720.88100
1.53-1.5613.50.37666740.9790.1060.3910.894100
1.56-1.613.50.31367260.9860.0880.3250.907100
1.6-1.6313.30.25567450.990.0720.2650.91999.9
1.63-1.6713.20.21767190.9910.0620.2260.93299.9
1.67-1.7212.90.18167310.9930.0520.1880.93899.8
1.72-1.7712.20.14867680.9950.0440.1550.96499.8
1.77-1.8312.40.12167440.9960.0350.1260.97199.9
1.83-1.8913.80.10267530.9980.0280.1060.981100
1.89-1.9713.90.08267640.9980.0230.0850.997100
1.97-2.0613.70.06668120.9990.0180.0681.044100
2.06-2.1713.50.05467800.9990.0150.0561.089100
2.17-2.313.20.04668130.9990.0130.0481.079100
2.3-2.4812.20.0467990.9990.0120.0421.04899.7
2.48-2.7312.90.03768400.9990.0110.0381.0399.9
2.73-3.12140.03468640.9990.010.0361.00499.9
3.12-3.9413.40.03269740.9990.0090.0330.978100
3.94-5012.20.03172250.9990.0090.0320.84299.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4.94 Å33.42 Å
Translation4.94 Å33.42 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASER2.7.17phasing
PHENIX1.11.1-2575refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6IMD

6imd


Resolution: 1.45→33.42 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 19.03
RfactorNum. reflection% reflection
Rfree0.2017 6719 4.96 %
Rwork0.1813 --
obs0.1823 135386 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 66.44 Å2 / Biso mean: 20.9807 Å2 / Biso min: 6.55 Å2
Refinement stepCycle: final / Resolution: 1.45→33.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5204 0 162 359 5725
Biso mean--27.51 29.92 -
Num. residues----651
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0145448
X-RAY DIFFRACTIONf_angle_d1.3137362
X-RAY DIFFRACTIONf_chiral_restr0.095847
X-RAY DIFFRACTIONf_plane_restr0.009937
X-RAY DIFFRACTIONf_dihedral_angle_d9.2012000
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.45-1.46620.25512020.2234385892
1.4662-1.48350.24132110.2073421297
1.4835-1.50150.22042240.2039420499
1.5015-1.52060.21882470.19734259100
1.5206-1.54060.23052140.19784225100
1.5406-1.56170.21632290.19684244100
1.5617-1.5840.23652210.19794298100
1.584-1.60760.21722530.19334255100
1.6076-1.63270.22672150.18794234100
1.6327-1.65950.2242280.18684271100
1.6595-1.68810.22432250.19154257100
1.6881-1.71880.22562110.18994270100
1.7188-1.75190.192210.18444293100
1.7519-1.78760.21182310.18084263100
1.7876-1.82650.20872300.18424262100
1.8265-1.8690.22522160.19124322100
1.869-1.91570.20682300.19064250100
1.9157-1.96750.22681980.19074329100
1.9675-2.02540.22432120.18674310100
2.0254-2.09080.18882230.17684285100
2.0908-2.16550.19372370.17654306100
2.1655-2.25220.19122320.17144330100
2.2522-2.35460.19342280.17894269100
2.3546-2.47870.19922130.17784357100
2.4787-2.6340.18422020.17864355100
2.634-2.83720.19972290.17934318100
2.8372-3.12260.19612410.1854351100
3.1226-3.5740.19532230.17514404100
3.574-4.50110.17932400.16454464100
4.5011-33.420.19782330.17834612100
Refinement TLS params.Method: refined / Origin x: 19.811 Å / Origin y: 83.405 Å / Origin z: 46.7968 Å
111213212223313233
T0.0814 Å20.0105 Å20.0304 Å2-0.0754 Å20.0101 Å2--0.122 Å2
L0.2463 °2-0.1767 °2-0.1409 °2-0.4859 °20.2957 °2--1.6323 °2
S-0.0722 Å °-0.0424 Å °-0.015 Å °0.0966 Å °0.0649 Å °-0.0033 Å °0.1456 Å °0.0821 Å °-0.0029 Å °
Refinement TLS groupSelection details: all

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