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- PDB-6kjz: Crystal structure of PDE4D catalytic domain complexed with compound 1 -

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Basic information

Entry
Database: PDB / ID: 6kjz
TitleCrystal structure of PDE4D catalytic domain complexed with compound 1
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4 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 / 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 / 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 / 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) / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 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. ...Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 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. / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-MKU / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.20000094865 Å
AuthorsHuang, Y.-Y. / He, X. / Luo, H.-B.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China21877134 China
National Natural Science Foundation of China81522041 China
National Natural Science Foundation of China21572279 China
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery and Optimization of alpha-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia.
Authors: Liang, J. / Huang, Y.Y. / Zhou, Q. / Gao, Y. / Li, Z. / Wu, D. / Yu, S. / Guo, L. / Chen, Z. / Huang, L. / Liang, S.H. / He, X. / Wu, R. / Luo, H.B.
History
DepositionJul 23, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2May 13, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.3Nov 22, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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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)76,6728
Polymers75,6722
Non-polymers1,0006
Water5,008278
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3364
Polymers37,8361
Non-polymers5003
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-34 kcal/mol
Surface area15080 Å2
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3364
Polymers37,8361
Non-polymers5003
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-33 kcal/mol
Surface area15140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.311, 79.700, 163.316
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: 37835.906 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-MKU / 5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-3,4-dihydro-2H,6H-pyrano[3,2-b]xanthen-6-one / 3-isomangostin


Mass: 410.460 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26O6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 2.55 Å3/Da / Density % sol: 51.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.4
Details: 0.1 M HEPES (pH 7.4), 0.1 M MgCl2, 15-20% PE G3350, 10% isopropanol, 25% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION NOVA / Wavelength: 1.5418 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Nov 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→22.15 Å / Num. obs: 40198 / % possible obs: 99 % / Redundancy: 3.6 % / Biso Wilson estimate: 27.1812120528 Å2 / Rmerge(I) obs: 0.052 / Net I/σ(I): 23.4
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.347 / Mean I/σ(I) obs: 2.16 / Num. unique obs: 4050 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
CrysalisPro38.41data reduction
CrysalisPro38.41data scaling
PHASER1.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQA

5wqa


Resolution: 2.20000094865→22.1481461147 Å / SU ML: 0.264293148852 / Cross valid method: FREE R-VALUE / σ(F): 1.370723182 / Phase error: 24.8855051815
RfactorNum. reflection% reflection
Rfree0.246253774685 1910 4.80418542647 %
Rwork0.201308334149 --
obs0.203477361054 39757 99.2089634177 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 34.2062049023 Å2
Refinement stepCycle: LAST / Resolution: 2.20000094865→22.1481461147 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5303 0 64 278 5645
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007689548049325477
X-RAY DIFFRACTIONf_angle_d0.8708839251017452
X-RAY DIFFRACTIONf_chiral_restr0.0449258933089849
X-RAY DIFFRACTIONf_plane_restr0.005593973201621012
X-RAY DIFFRACTIONf_dihedral_angle_d15.39274224133292
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.21-2.2550.3198338305061190.222627X-RAY DIFFRACTION98.2117310443
2.255-2.31590.3114772052321370.2555138339112639X-RAY DIFFRACTION99.0720913633
2.3159-2.38390.2971547722241260.2351074045332713X-RAY DIFFRACTION99.8241912799
2.3839-2.46080.2416618413941410.2227613801832669X-RAY DIFFRACTION99.9644254714
2.4608-2.54860.2455402378291160.2346885626052724X-RAY DIFFRACTION99.8944776644
2.5486-2.65050.3091278865221480.2292369728932669X-RAY DIFFRACTION100
2.6505-2.77090.2994143336551560.2303805695772675X-RAY DIFFRACTION99.9646892655
2.7709-2.91670.2759631149391250.2279673129892712X-RAY DIFFRACTION99.7889553289
2.9167-3.0990.2539354221851520.2221486498392718X-RAY DIFFRACTION99.7913769124
3.099-3.33750.2537543857961230.2181736480592715X-RAY DIFFRACTION99.7539543058
3.3375-3.6720.2558247792771300.1980796113542751X-RAY DIFFRACTION99.7576177285
3.672-4.20020.2245926532551430.1811132035612723X-RAY DIFFRACTION99.4103364551
4.2002-5.280.2105236569921490.1574099195982741X-RAY DIFFRACTION98.6348122867
5.28-22.140.1876056329981450.1599924439282771X-RAY DIFFRACTION95.2629859523

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