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- PDB-3sl8: Crystal structure of the catalytic domain of PDE4D2 with compound 10o -

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Basic information

Entry
Database: PDB / ID: 3sl8
TitleCrystal structure of the catalytic domain of PDE4D2 with compound 10o
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHydrolase/Hydrolase Inhibitor / catalytic mechanism / cAMP hydrolysis / Hydrolase-Hydrolase Inhibitor complex
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 / positive regulation of heart rate / adrenergic receptor signaling pathway / heterocyclic compound binding / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / negative regulation of peptidyl-serine phosphorylation / 3',5'-cyclic-nucleotide phosphodiesterase activity / DARPP-32 events / 3',5'-cyclic-GMP phosphodiesterase activity / calcium channel regulator activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to cAMP / calcium channel complex / cellular response to epinephrine stimulus / positive regulation of interleukin-2 production / cAMP-mediated signaling / regulation of heart rate / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / G alpha (s) signalling events / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / membrane / nucleus / metal ion binding / 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-JN7 / DI(HYDROXYETHYL)ETHER / PHOSPHATE ION / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsFeil, S.F.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Thiophene inhibitors of PDE4: Crystal structures show a second binding mode at the catalytic domain of PDE4D2.
Authors: Nankervis, J.L. / Feil, S.C. / Hancock, N.C. / Zheng, Z. / Ng, H.L. / Morton, C.J. / Holien, J.K. / Ho, P.W. / Frazzetto, M.M. / Jennings, I.G. / Manallack, D.T. / Martin, T.J. / Thompson, P.E. / Parker, M.W.
History
DepositionJun 24, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2011Provider: repository / Type: Initial release
Revision 1.1Dec 14, 2011Group: Database references
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_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 / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_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
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)170,88252
Polymers166,0964
Non-polymers4,78648
Water4,252236
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,02818
Polymers41,5241
Non-polymers1,50417
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3347
Polymers41,5241
Non-polymers8106
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4759
Polymers41,5241
Non-polymers9518
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,04418
Polymers41,5241
Non-polymers1,52017
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.140, 111.650, 161.740
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
DetailsAS PER THE AUTHORS THE BIOLOGICAL ASSEMBLY IS UNKNOWN

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 41523.887 Da / Num. of mol.: 4 / Fragment: Catalytic domain, UNP residues 381-741
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) Star Rosetta
References: UniProt: Q08499, 3',5'-cyclic-nucleotide phosphodiesterase

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Non-polymers , 7 types, 284 molecules

#2: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 30 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical
ChemComp-JN7 / 3-cyclopentyl 6-ethenyl 2-[(thiophen-2-ylacetyl)amino]-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate


Mass: 460.566 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H24N2O5S2
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 236 / 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: 2.95 Å3/Da / Density % sol: 58.24 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 20% PEG 3350, 25% (v/v) ethylene glycol, 10% (v/v) isopropanol, 100 mM HEPES, pH 7.5, vapor diffusion, hanging drop, temperature 294K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD
RadiationMonochromator: K-B pair of biomorph mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→20 Å / Num. obs: 53415 / % possible obs: 95.5 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.7 % / Biso Wilson estimate: 46.462 Å2 / Rmerge(I) obs: 0.088 / Net I/σ(I): 16.48
Reflection shell
Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique obsDiffraction-ID% possible all
2.6-2.70.6663.04281775417192.2
2.7-2.80.4114.26295005015198.6
2.8-2.90.3165.33258984366198.6
2.9-30.2616.43226123806198.2
3-3.10.2137.8198613344198.4
3.1-3.20.1769.26172082897198.4
3.2-3.30.14311.44152712570197.7
3.3-3.40.12513.08134172280197.8
3.4-3.60.10515.68185963628192.7
3.6-40.07920.67262345204191.2
4-60.04531.546191010500196.3
6-100.03239.96203603517194.5
10-200.02453.254733871179.1

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.5_2refinement
PDB_EXTRACT3.1data extraction
Blu-Icedata collection
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→19.763 Å / Occupancy max: 1 / Occupancy min: 0.29 / FOM work R set: 0.8078 / SU ML: 0.38 / σ(F): 1.99 / Phase error: 26.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2728 2672 5 %RANDOM
Rwork0.1962 ---
obs0.2 53409 95.8 %-
all-55750 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 63.818 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso max: 118.82 Å2 / Biso mean: 43.0122 Å2 / Biso min: 12.39 Å2
Baniso -1Baniso -2Baniso -3
1-1.6253 Å2-0 Å20 Å2
2---4.2818 Å2-0 Å2
3---2.6566 Å2
Refinement stepCycle: LAST / Resolution: 2.6→19.763 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10514 0 284 236 11034
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00810994
X-RAY DIFFRACTIONf_angle_d1.16614871
X-RAY DIFFRACTIONf_chiral_restr0.0771693
X-RAY DIFFRACTIONf_plane_restr0.0071898
X-RAY DIFFRACTIONf_dihedral_angle_d20.4784033
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 19

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6-2.64720.26521410.19072667280898
2.6472-2.6980.41411250.30592367249286
2.698-2.75290.35091450.24242739288499
2.7529-2.81260.2971410.20212705284699
2.8126-2.87780.26151440.18452723286798
2.8778-2.94960.26781420.19322700284298
2.9496-3.0290.31111430.1912720286398
3.029-3.11780.30941450.20292748289398
3.1178-3.21810.27291420.18422704284698
3.2181-3.33260.27111430.18942707285098
3.3326-3.46530.33141330.21732546267992
3.4653-3.62210.26391400.20672672281296
3.6221-3.81180.31331370.22122592272993
3.8118-4.04870.28331320.21742503263590
4.0487-4.35820.24191430.16772713285697
4.3582-4.79110.2411420.15712710285296
4.7911-5.47150.22011440.1722723286796
5.4715-6.84560.26581420.19222712285495
6.8456-19.7630.19821480.15452786293494

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