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- PDB-5k32: PDE4D crystal structure in complex with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 5k32
TitlePDE4D crystal structure in complex with small molecule inhibitor
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / phosphodiesterases / 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-6Q2 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsSegarra, V. / Hernandez, B. / Roberts, R. / Gracia, J. / Soler, M. / Bonin, I. / Aymami, J.
CitationJournal: J. Med. Chem. / Year: 2018
Title: 4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships.
Authors: Roberts, R.S. / Sevilla, S. / Ferrer, M. / Taltavull, J. / Hernandez, B. / Segarra, V. / Gracia, J. / Lehner, M.D. / Gavalda, A. / Andres, M. / Cabedo, J. / Vilella, D. / Eichhorn, P. / ...Authors: Roberts, R.S. / Sevilla, S. / Ferrer, M. / Taltavull, J. / Hernandez, B. / Segarra, V. / Gracia, J. / Lehner, M.D. / Gavalda, A. / Andres, M. / Cabedo, J. / Vilella, D. / Eichhorn, P. / Calama, E. / Carcasona, C. / Miralpeix, M.
History
DepositionMay 19, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Mar 29, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2018Group: Advisory / Database references
Category: citation / citation_author / pdbx_unobs_or_zero_occ_atoms
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 4, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 10, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_struct_conn_angle / pdbx_unobs_or_zero_occ_atoms / struct_conn
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_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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,69540
Polymers74,8392
Non-polymers2,85638
Water8,485471
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8300 Å2
ΔGint-11 kcal/mol
Surface area28020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.967, 79.739, 163.845
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 / DPDE3 / PDE43


Mass: 37419.453 Da / Num. of mol.: 2 / Fragment: UNP residues 88-411
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, 509 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-6Q2 / 4-[(3-methoxyphenyl)amino]-2-phenyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one


Mass: 345.394 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H19N3O2
#5: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 32 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 471 / 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: 2.64 Å3/Da / Density % sol: 53.39 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5
Details: 19% PEG 3350, 36 % Ethylene Glycol and 10 % Isopropanol as a precipitant

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Data collection

DiffractionMean temperature: 293 K
Diffraction sourceSource: ROTATING ANODE / Type: OTHER / Wavelength: 1.54 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jun 7, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.99→20 Å / Num. obs: 245085 / % possible obs: 94.7 % / Redundancy: 3.1 % / Rrim(I) all: 0.1 / Net I/σ(I): 1.7
Reflection shellResolution: 1.99→2.1 Å / Rrim(I) all: 0.59

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
PDB_EXTRACT3.2data extraction
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TB7

1tb7


Resolution: 1.99→20 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.86 / SU B: 5.129 / SU ML: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.218 / ESU R Free: 0.201 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2813 2627 5.1 %RANDOM
Rwork0.2198 ---
obs0.2229 49055 94.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 64.74 Å2 / Biso mean: 30.36 Å2 / Biso min: 5.36 Å2
Baniso -1Baniso -2Baniso -3
1-1.93 Å20 Å20 Å2
2---0.06 Å20 Å2
3----1.86 Å2
Refinement stepCycle: final / Resolution: 1.99→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5207 0 184 471 5862
Biso mean--37.47 37.1 -
Num. residues----643
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0215485
X-RAY DIFFRACTIONr_angle_refined_deg1.8481.9637385
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0895643
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.86225.111270
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.8715950
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.721526
X-RAY DIFFRACTIONr_chiral_restr0.1270.2838
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024062
X-RAY DIFFRACTIONr_nbd_refined0.2190.22724
X-RAY DIFFRACTIONr_nbtor_refined0.2960.23687
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1910.2427
X-RAY DIFFRACTIONr_metal_ion_refined0.1060.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2590.239
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2370.220
X-RAY DIFFRACTIONr_mcbond_it1.191.53387
X-RAY DIFFRACTIONr_mcangle_it1.69525248
X-RAY DIFFRACTIONr_scbond_it2.84932436
X-RAY DIFFRACTIONr_scangle_it3.7574.52133
LS refinement shellResolution: 1.99→2.041 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.397 174 -
Rwork0.247 3560 -
all-3734 -
obs--94.6 %

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