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- PDB-3sl4: Crystal structure of the catalytic domain of PDE4D2 with compound 10D -

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Basic information

Entry
Database: PDB / ID: 3sl4
TitleCrystal structure of the catalytic domain of PDE4D2 with compound 10D
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHydrolase/Inhibitor / catalytic mechanism / cAMP hydrolysis / Hydrolase-Inhibitor complex
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 / 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 relaxation of cardiac muscle / negative regulation of heart contraction / 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 / calcium channel complex / cellular response to epinephrine stimulus / 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) / 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-JN4 / DI(HYDROXYETHYL)ETHER / PHOSPHATE ION / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / molrep / Resolution: 1.9 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
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)173,44286
Polymers166,0964
Non-polymers7,34782
Water8,413467
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,41724
Polymers41,5241
Non-polymers1,89323
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)43,16018
Polymers41,5241
Non-polymers1,63617
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)43,09817
Polymers41,5241
Non-polymers1,57416
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)43,76727
Polymers41,5241
Non-polymers2,24326
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.375, 111.088, 161.215
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 , 8 types, 549 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 51 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#7: Chemical
ChemComp-JN4 / ethenyl 6-(ethenylcarbamoyl)-2-[(phenylacetyl)amino]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate


Mass: 411.474 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H21N3O4S
#8: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 467 / 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: 57.99 %
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 / Date: Feb 17, 2010
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: 1.9→50 Å / Num. obs: 139220 / % possible obs: 99.1 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5 % / Rmerge(I) obs: 0.065 / Χ2: 1.063 / Net I/σ(I): 10.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.9-1.974.80.606137761.058199.2
1.97-2.054.80.396137231.05198.8
2.05-2.144.80.273136761.105198.3
2.14-2.254.80.195137811.184198.5
2.25-2.394.80.15137561.22198.7
2.39-2.584.80.119139121.119199.4
2.58-2.8450.09139981.113199.7
2.84-3.255.30.067140541.0551100
3.25-4.095.60.048141870.9511100
4.09-505.30.035143570.841198.1

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.5_2refinement
PDB_EXTRACT3.1data extraction
Blu-Icedata collection
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: molrep / Resolution: 1.9→32.621 Å / Occupancy max: 1 / Occupancy min: 0.08 / FOM work R set: 0.8499 / SU ML: 0.25 / σ(F): 0.05 / Phase error: 22.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2274 6400 5.03 %RANDOM
Rwork0.1942 ---
obs0.1959 127229 90.5 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.572 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso max: 88.64 Å2 / Biso mean: 32.3233 Å2 / Biso min: 10.87 Å2
Baniso -1Baniso -2Baniso -3
1-1.2817 Å2-0 Å20 Å2
2---2.1077 Å2-0 Å2
3---0.826 Å2
Refinement stepCycle: LAST / Resolution: 1.9→32.621 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10542 0 445 467 11454
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00711168
X-RAY DIFFRACTIONf_angle_d1.00115050
X-RAY DIFFRACTIONf_chiral_restr0.0661701
X-RAY DIFFRACTIONf_plane_restr0.0071912
X-RAY DIFFRACTIONf_dihedral_angle_d18.5864085
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9-1.9220.30121440.24713348349275
1.922-1.94460.29721780.24393407358577
1.9446-1.96830.30182010.22623541374281
1.9683-1.99330.27281830.22023688387183
1.9933-2.01950.27372140.21313717393185
2.0195-2.04710.26261890.20633763395286
2.0471-2.07640.24041930.20613781397486
2.0764-2.10740.25581790.20373827400686
2.1074-2.14030.22952090.20153841405088
2.1403-2.17540.23911940.20434026422090
2.1754-2.21290.24672170.19883946416390
2.2129-2.25310.2522080.20333912412089
2.2531-2.29640.24832100.20483898410888
2.2964-2.34330.25751860.19623979416590
2.3433-2.39420.22711950.19634037423291
2.3942-2.44990.23372310.20124004423590
2.4499-2.51120.25322420.20164008425091
2.5112-2.5790.25342130.19294073428692
2.579-2.65490.21192410.18544095433693
2.6549-2.74050.21692680.18854117438594
2.7405-2.83840.21842180.18254252447095
2.8384-2.9520.22562220.20284167438994
2.952-3.08630.23762060.19074306451296
3.0863-3.24880.21222360.19874326456297
3.2488-3.45220.23032210.19244395461698
3.4522-3.71840.23062210.18624469469099
3.7184-4.09190.20672520.1774420467299
4.0919-4.68250.18662220.16334484470699
4.6825-5.89380.1892420.194532477499
5.8938-32.6210.20922650.18734470473595

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