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- PDB-6im6: Crystal structure of PDE4D complexed with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 6im6
TitleCrystal structure of PDE4D complexed with a novel inhibitor
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE4D / Inhibitor / Complex / Apremilast / 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 / 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 heart contraction / negative regulation of relaxation of cardiac muscle / 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 / cellular response to epinephrine stimulus / calcium channel complex / 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-AH3 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.702 Å
AuthorsZhang, X.L. / Su, H.X. / Xu, Y.C.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.
Authors: Zhang, X. / Dong, G. / Li, H. / Chen, W. / Li, J. / Feng, C. / Gu, Z. / Zhu, F. / Zhang, R. / Li, M. / Tang, W. / Liu, H. / Xu, Y.
History
DepositionOct 22, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 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
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.ptnr1_symmetry / _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_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)81,69823
Polymers80,1932
Non-polymers1,50521
Water6,089338
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4790 Å2
ΔGint-75 kcal/mol
Surface area27000 Å2
Unit cell
Length a, b, c (Å)58.081, 80.346, 163.350
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / PDE4D / DPDE3 / PDE43


Mass: 40096.355 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) / Strain (production host): BL21 (DE3)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 359 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.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-AH3 / 7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde


Mass: 235.279 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H17NO3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 338 / 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: 2.38 Å3/Da / Density % sol: 48.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M HEPES, 0.2 M MgCl2, 10% isopropanol, 30% EG, 18% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.978 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.702→40.173 Å / Num. obs: 84517 / % possible obs: 90.34 % / Redundancy: 12.4 % / Net I/σ(I): 8.4
Reflection shellResolution: 1.702→1.723 Å

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementResolution: 1.702→40.173 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.33
RfactorNum. reflection% reflection
Rfree0.2404 3843 5.03 %
Rwork0.2107 --
obs0.2122 76437 90.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.702→40.173 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5178 0 92 338 5608
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075361
X-RAY DIFFRACTIONf_angle_d0.7537270
X-RAY DIFFRACTIONf_dihedral_angle_d3.2223255
X-RAY DIFFRACTIONf_chiral_restr0.046840
X-RAY DIFFRACTIONf_plane_restr0.005930
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7018-1.72340.2818690.27221336X-RAY DIFFRACTION46
1.7234-1.7460.3074950.26991638X-RAY DIFFRACTION56
1.746-1.770.3274990.25421799X-RAY DIFFRACTION61
1.77-1.79520.26861100.26411954X-RAY DIFFRACTION67
1.7952-1.8220.32891010.24362122X-RAY DIFFRACTION72
1.822-1.85050.29011090.24922196X-RAY DIFFRACTION76
1.8505-1.88080.26511320.25652397X-RAY DIFFRACTION80
1.8808-1.91330.30851520.25952635X-RAY DIFFRACTION90
1.9133-1.94810.26361300.25142802X-RAY DIFFRACTION95
1.9481-1.98550.32941600.24182933X-RAY DIFFRACTION99
1.9855-2.02610.25221320.24132966X-RAY DIFFRACTION100
2.0261-2.07010.27341680.23162941X-RAY DIFFRACTION100
2.0701-2.11830.27081660.22882933X-RAY DIFFRACTION100
2.1183-2.17120.26931570.22142954X-RAY DIFFRACTION100
2.1712-2.22990.26791490.22052969X-RAY DIFFRACTION100
2.2299-2.29550.24771510.22222945X-RAY DIFFRACTION100
2.2955-2.36960.29321660.21892950X-RAY DIFFRACTION100
2.3696-2.45430.20831400.20842955X-RAY DIFFRACTION100
2.4543-2.55260.25231690.21412977X-RAY DIFFRACTION100
2.5526-2.66870.23461470.22032995X-RAY DIFFRACTION100
2.6687-2.80940.2641620.20712943X-RAY DIFFRACTION100
2.8094-2.98530.20651670.21072982X-RAY DIFFRACTION99
2.9853-3.21580.23391640.20452995X-RAY DIFFRACTION100
3.2158-3.53920.21141750.19182988X-RAY DIFFRACTION99
3.5392-4.05090.20181610.18213024X-RAY DIFFRACTION100
4.0509-5.10210.19531610.16743052X-RAY DIFFRACTION99
5.1021-40.18420.20411510.19253213X-RAY DIFFRACTION99

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