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- PDB-6f8v: Crystal structure of the PDE4D catalytic domain in complex with G... -

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Basic information

Entry
Database: PDB / ID: 6f8v
TitleCrystal structure of the PDE4D catalytic domain in complex with GEBR-18b
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 / negative regulation of peptidyl-serine phosphorylation / 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 / DARPP-32 events / 3',5'-cyclic-GMP phosphodiesterase activity / calcium channel regulator activity / 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 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 / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / nucleus / membrane / 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-D0B / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 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.ptnr2_symmetry / _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)80,33310
Polymers79,2502
Non-polymers1,0838
Water8,737485
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 area2060 Å2
ΔGint-113 kcal/mol
Surface area27680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.558, 98.314, 120.089
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.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-D0B / 3-[3-(3-cyclopentyloxy-4-methoxy-phenyl)pyrazol-1-yl]-1-[(2~{R},6~{R})-2,6-dimethylmorpholin-4-yl]propan-1-one


Mass: 427.537 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H33N3O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 485 / 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: 2.4 Å3/Da / Density % sol: 48.84 %
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: May 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→45.493 Å / Num. obs: 64377 / % possible obs: 99.4 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.096 / Net I/σ(I): 11.2
Reflection shellResolution: 1.85→2.248 Å

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Processing

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

6f6u


Resolution: 1.85→45.493 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.89
RfactorNum. reflection% reflection
Rfree0.2544 3274 5.09 %
Rwork0.2047 --
obs0.2072 64377 97.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.85→45.493 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5251 0 68 486 5805
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075480
X-RAY DIFFRACTIONf_angle_d0.9927458
X-RAY DIFFRACTIONf_dihedral_angle_d14.1032028
X-RAY DIFFRACTIONf_chiral_restr0.04857
X-RAY DIFFRACTIONf_plane_restr0.005954
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.87760.41271400.35862547X-RAY DIFFRACTION96
1.8776-1.9070.51831320.47022239X-RAY DIFFRACTION83
1.907-1.93820.60051140.53922329X-RAY DIFFRACTION87
1.9382-1.97160.36231590.29762617X-RAY DIFFRACTION98
1.9716-2.00750.29221540.23672637X-RAY DIFFRACTION99
2.0075-2.04610.26191390.23512651X-RAY DIFFRACTION99
2.0461-2.08790.561290.36882508X-RAY DIFFRACTION93
2.0879-2.13330.2491500.21092690X-RAY DIFFRACTION100
2.1333-2.18290.26451040.19962735X-RAY DIFFRACTION100
2.1829-2.23750.29351350.23082627X-RAY DIFFRACTION97
2.2375-2.2980.36831620.2782543X-RAY DIFFRACTION95
2.298-2.36560.26341580.18012668X-RAY DIFFRACTION100
2.3656-2.4420.25151530.17762703X-RAY DIFFRACTION100
2.442-2.52920.21991280.17892725X-RAY DIFFRACTION100
2.5292-2.63050.23251500.18132703X-RAY DIFFRACTION100
2.6305-2.75020.24061380.19952731X-RAY DIFFRACTION100
2.7502-2.89520.24981510.1872722X-RAY DIFFRACTION100
2.8952-3.07650.20771370.1822744X-RAY DIFFRACTION100
3.0765-3.3140.22881340.17682745X-RAY DIFFRACTION100
3.314-3.64740.23451270.17952766X-RAY DIFFRACTION100
3.6474-4.17480.20071580.16432748X-RAY DIFFRACTION100
4.1748-5.25860.18661660.1472789X-RAY DIFFRACTION100
5.2586-45.50690.16821560.16472936X-RAY DIFFRACTION100

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