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

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Basic information

Entry
Database: PDB / ID: 6imr
TitleCrystal structure of PDE4D complexed with a novel inhibitor
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE4D / Inhibitor / Complex / HYDROLASE / 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-AJX / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.503 Å
AuthorsZhang, X.L. / Su, H.X. / Xu, Y.C.
Funding support China, 1items
OrganizationGrant numberCountry
China
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 23, 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.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

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)81,99822
Polymers80,1932
Non-polymers1,80520
Water8,053447
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4700 Å2
ΔGint-60 kcal/mol
Surface area26800 Å2
Unit cell
Length a, b, c (Å)58.120, 80.624, 163.669
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, 467 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-AJX / (1S)-1-[3-(1H-indol-3-yl)propyl]-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde


Mass: 378.464 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26N2O3
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 447 / 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: 2.39 Å3/Da / Density % sol: 48.55 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
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: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.503→30.902 Å / Num. obs: 122545 / % possible obs: 99.54 % / Redundancy: 13 % / Net I/σ(I): 10.6
Reflection shellResolution: 1.503→1.52 Å

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementResolution: 1.503→30.902 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.84
RfactorNum. reflection% reflection
Rfree0.2366 6014 4.91 %
Rwork0.2112 --
obs0.2124 122380 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.503→30.902 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5121 0 116 447 5684
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065379
X-RAY DIFFRACTIONf_angle_d0.7787297
X-RAY DIFFRACTIONf_dihedral_angle_d3.3213239
X-RAY DIFFRACTIONf_chiral_restr0.048842
X-RAY DIFFRACTIONf_plane_restr0.005932
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5031-1.52020.23951730.23913336X-RAY DIFFRACTION87
1.5202-1.5380.28482110.2443822X-RAY DIFFRACTION100
1.538-1.55680.28162330.24473827X-RAY DIFFRACTION100
1.5568-1.57650.25852000.24053839X-RAY DIFFRACTION100
1.5765-1.59720.25931980.23973840X-RAY DIFFRACTION100
1.5972-1.61910.25571950.23513887X-RAY DIFFRACTION100
1.6191-1.64230.32681940.2363845X-RAY DIFFRACTION100
1.6423-1.66680.24941990.23543859X-RAY DIFFRACTION100
1.6668-1.69280.27722140.23863824X-RAY DIFFRACTION100
1.6928-1.72060.26942150.24043876X-RAY DIFFRACTION100
1.7206-1.75020.28352020.23333847X-RAY DIFFRACTION100
1.7502-1.78210.26062010.22163857X-RAY DIFFRACTION100
1.7821-1.81630.25382030.22813890X-RAY DIFFRACTION100
1.8163-1.85340.22691890.23083847X-RAY DIFFRACTION100
1.8534-1.89370.24771860.22973888X-RAY DIFFRACTION100
1.8937-1.93770.2572170.23213876X-RAY DIFFRACTION100
1.9377-1.98620.2721880.23193896X-RAY DIFFRACTION100
1.9862-2.03990.2722090.22583851X-RAY DIFFRACTION100
2.0399-2.09990.24542230.22043868X-RAY DIFFRACTION100
2.0999-2.16770.23172260.21043868X-RAY DIFFRACTION100
2.1677-2.24510.20371930.21123907X-RAY DIFFRACTION100
2.2451-2.3350.24641800.20883913X-RAY DIFFRACTION100
2.335-2.44120.22562090.20793920X-RAY DIFFRACTION100
2.4412-2.56980.23721870.20833909X-RAY DIFFRACTION100
2.5698-2.73080.23922110.20883921X-RAY DIFFRACTION100
2.7308-2.94140.22021720.20873966X-RAY DIFFRACTION100
2.9414-3.23720.22451970.20433984X-RAY DIFFRACTION100
3.2372-3.70490.22331930.19263967X-RAY DIFFRACTION100
3.7049-4.66520.1921920.18064024X-RAY DIFFRACTION100
4.6652-30.90880.21692040.18894212X-RAY DIFFRACTION100

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