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- PDB-6akr: Crystal structure of the PDE4D catalytic domain in complex with o... -

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Basic information

Entry
Database: PDB / ID: 6akr
TitleCrystal structure of the PDE4D catalytic domain in complex with osthole
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / phosphodiesterase 4d
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) / 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
7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.326 Å
AuthorsWang, S. / Huo, Y.W. / Xie, Y.
Funding support United States, China, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL116849 United States
National Natural Science Foundation of China21777192 China
National Natural Science Foundation of China2017YFA0205501 China
National Natural Science Foundation of China31500623 China
CitationJournal: Sci.Signal. / Year: 2020
Title: Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma.
Authors: Wang, S. / Xie, Y. / Huo, Y.W. / Li, Y. / Abel, P.W. / Jiang, H. / Zou, X. / Jiao, H.Z. / Kuang, X. / Wolff, D.W. / Huang, Y.G. / Casale, T.B. / Panettieri Jr., R.A. / Wei, T. / Cao, Z. / Tu, Y.
History
DepositionSep 3, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 2, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _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
Revision 1.2Mar 23, 2022Group: Author supporting evidence / Database references / Category: database_2 / pdbx_audit_support
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.3Nov 22, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)168,73316
Polymers167,2334
Non-polymers1,50012
Water7,278404
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1834
Polymers41,8081
Non-polymers3753
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-78 kcal/mol
Surface area14790 Å2
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1834
Polymers41,8081
Non-polymers3753
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-79 kcal/mol
Surface area15090 Å2
MethodPISA
3
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1834
Polymers41,8081
Non-polymers3753
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area240 Å2
ΔGint-78 kcal/mol
Surface area14750 Å2
MethodPISA
4
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1834
Polymers41,8081
Non-polymers3753
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-78 kcal/mol
Surface area14650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.765, 111.429, 159.669
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 41808.242 Da / Num. of mol.: 4 / Fragment: UNP residues 381-740
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D / Production host: Escherichia coli (E. coli)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-A0O / 7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one


Mass: 244.286 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H16O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 404 / Source method: isolated from a natural source / Formula: H2O

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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: 2.93 Å3/Da / Density % sol: 58.02 %
Crystal growTemperature: 277.15 K / Method: evaporation
Details: 0.1M HEPES, 18% PEG3350, 25% ethylene glycol, 10% isopropanol, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 76639 / % possible obs: 99.8 % / Redundancy: 6.1 % / Rmerge(I) obs: 0.094 / Net I/σ(I): 16.3
Reflection shellResolution: 2.3→2.38 Å / Rmerge(I) obs: 0.44 / Num. unique obs: 7464

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Processing

Software
NameVersionClassification
PHENIX1.8_1069refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Q9M

1q9m


Resolution: 2.326→48.643 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.79
RfactorNum. reflection% reflection
Rfree0.2204 2019 2.63 %
Rwork0.1873 --
obs0.1882 76639 99.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.326→48.643 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10626 0 0 404 11030
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00810838
X-RAY DIFFRACTIONf_angle_d1.0414724
X-RAY DIFFRACTIONf_dihedral_angle_d15.544021
X-RAY DIFFRACTIONf_chiral_restr0.0681688
X-RAY DIFFRACTIONf_plane_restr0.0041894
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3258-2.3840.24641170.21814287X-RAY DIFFRACTION42
2.384-2.44850.25441410.21445207X-RAY DIFFRACTION51
2.4485-2.52050.30341420.22455249X-RAY DIFFRACTION51
2.5205-2.60190.29971440.21755313X-RAY DIFFRACTION52
2.6019-2.69480.27491430.20345298X-RAY DIFFRACTION52
2.6948-2.80270.25451450.19565322X-RAY DIFFRACTION52
2.8027-2.93030.24391440.19935325X-RAY DIFFRACTION52
2.9303-3.08470.21571440.19595307X-RAY DIFFRACTION52
3.0847-3.2780.24311440.20135324X-RAY DIFFRACTION52
3.278-3.5310.20171460.18665345X-RAY DIFFRACTION52
3.531-3.88620.20821450.18135352X-RAY DIFFRACTION52
3.8862-4.44820.20281460.16375388X-RAY DIFFRACTION52
4.4482-5.6030.18681520.17635718X-RAY DIFFRACTION56
5.603-48.65380.1841660.16866185X-RAY DIFFRACTION60

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