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- PDB-6f8w: Crystal structure of the PDE4D catalytic domain in complex with G... -

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Basic information

Entry
Database: PDB / ID: 6f8w
TitleCrystal structure of the PDE4D catalytic domain in complex with GEBR-18a
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4 / catalytic domain / inhibitor / GEBR
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 / heterocyclic compound binding / positive regulation of heart rate / adrenergic receptor signaling pathway / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-serine phosphorylation / cAMP catabolic process / 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 / cAMP-mediated signaling / 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 / 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-D0E / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.601 Å
AuthorsProsdocimi, T. / Donini, S. / Parisini, E.
CitationJournal: Biochemistry / Year: 2018
Title: Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.
Authors: Prosdocimi, T. / Mollica, L. / Donini, S. / Semrau, M.S. / Lucarelli, A.P. / Aiolfi, E. / Cavalli, A. / Storici, P. / Alfei, S. / Brullo, C. / Bruno, O. / Parisini, E.
History
DepositionDec 13, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1May 23, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: 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 / pdbx_struct_conn_angle / 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_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.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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.ptnr3_symmetry / _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_symmetry

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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)80,30111
Polymers79,2502
Non-polymers1,0519
Water8,863492
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: Dimer is already characterized and validated in the literature.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-111 kcal/mol
Surface area28060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.039, 98.717, 120.765
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: 39624.945 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(DE3) (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.: 5 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-D0E / 3-[3-(3-cyclopentyloxy-4-methoxy-phenyl)pyrazol-1-yl]-1-morpholin-4-yl-propan-1-one


Mass: 399.483 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H29N3O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 492 / 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: 2.45 Å3/Da / Density % sol: 49.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: Hepes PEG 3350 Magnesium Chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 20, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→45.69 Å / Num. obs: 196940 / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 12.3
Reflection shellResolution: 1.6→1.889 Å

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6F6U

6f6u


Resolution: 1.601→45.69 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 0.96 / Phase error: 23.7
RfactorNum. reflection% reflection
Rfree0.219 9853 5 %
Rwork0.1913 --
obs0.1927 196940 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.601→45.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5268 0 65 494 5827
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065555
X-RAY DIFFRACTIONf_angle_d0.9287569
X-RAY DIFFRACTIONf_dihedral_angle_d14.4032082
X-RAY DIFFRACTIONf_chiral_restr0.037864
X-RAY DIFFRACTIONf_plane_restr0.005970
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6006-1.61880.36093220.326086X-RAY DIFFRACTION97
1.6188-1.63780.34293310.30986273X-RAY DIFFRACTION100
1.6378-1.65780.33253320.29776271X-RAY DIFFRACTION100
1.6578-1.67880.29113270.28486234X-RAY DIFFRACTION100
1.6788-1.70080.32063310.27686271X-RAY DIFFRACTION100
1.7008-1.72410.29943320.27146257X-RAY DIFFRACTION100
1.7241-1.74880.28933190.25046216X-RAY DIFFRACTION100
1.7488-1.77490.27843300.24156250X-RAY DIFFRACTION100
1.7749-1.80260.25183260.23766257X-RAY DIFFRACTION99
1.8026-1.83220.28883270.23446205X-RAY DIFFRACTION99
1.8322-1.86380.28743260.22716269X-RAY DIFFRACTION100
1.8638-1.89770.25873280.23466273X-RAY DIFFRACTION100
1.8977-1.93420.29313290.2356216X-RAY DIFFRACTION100
1.9342-1.97360.2673280.21726292X-RAY DIFFRACTION100
1.9736-2.01660.24673280.20196241X-RAY DIFFRACTION100
2.0166-2.06350.24163270.19726225X-RAY DIFFRACTION100
2.0635-2.11510.21453320.19056275X-RAY DIFFRACTION99
2.1151-2.17230.22243350.1876239X-RAY DIFFRACTION100
2.1723-2.23620.23333320.18726252X-RAY DIFFRACTION100
2.2362-2.30830.24013200.19256199X-RAY DIFFRACTION99
2.3083-2.39080.21233270.18696250X-RAY DIFFRACTION99
2.3908-2.48660.21123310.18956238X-RAY DIFFRACTION99
2.4866-2.59970.23053310.18846197X-RAY DIFFRACTION99
2.5997-2.73680.21993330.18966203X-RAY DIFFRACTION99
2.7368-2.90820.23123330.19446246X-RAY DIFFRACTION100
2.9082-3.13270.20893210.19236251X-RAY DIFFRACTION100
3.1327-3.44790.2023320.18326226X-RAY DIFFRACTION99
3.4479-3.94650.18913290.17336214X-RAY DIFFRACTION99
3.9465-4.97130.15983250.14756224X-RAY DIFFRACTION99
4.9713-45.70820.19173290.16356237X-RAY DIFFRACTION100

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