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

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Basic information

Entry
Database: PDB / ID: 6imd
TitleCrystal structure of PDE4D complexed with a novel inhibitor
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE4D / Inhibitor / Complex / 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-AH9 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.499 Å
AuthorsZhang, X. / Su, H. / Xu, Y.
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 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_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.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)81,54621
Polymers80,1932
Non-polymers1,35319
Water8,179454
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2030 Å2
ΔGint-112 kcal/mol
Surface area27190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.400, 80.357, 163.441
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, 473 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-AH9 / 6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde


Mass: 221.252 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H15NO3
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 454 / 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: 48.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M HEPES, 0.2 M MaCl2, 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: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.499→39.017 Å / Num. obs: 123931 / % possible obs: 92.73 % / Redundancy: 12.9 % / CC1/2: 0.82 / Net I/σ(I): 7.9
Reflection shellResolution: 1.499→1.516 Å

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementResolution: 1.499→39.017 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.37
RfactorNum. reflection% reflection
Rfree0.1903 5684 4.95 %
Rwork0.1676 --
obs0.1688 114867 92.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.499→39.017 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5178 0 82 454 5714
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0155371
X-RAY DIFFRACTIONf_angle_d1.3387291
X-RAY DIFFRACTIONf_dihedral_angle_d14.7421962
X-RAY DIFFRACTIONf_chiral_restr0.105843
X-RAY DIFFRACTIONf_plane_restr0.008934
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4993-1.51640.2471860.20361673X-RAY DIFFRACTION43
1.5164-1.53420.26351180.20531971X-RAY DIFFRACTION52
1.5342-1.55290.21951110.20732389X-RAY DIFFRACTION61
1.5529-1.57260.21051550.1972511X-RAY DIFFRACTION65
1.5726-1.59330.21851550.19353094X-RAY DIFFRACTION79
1.5933-1.61510.2331880.193584X-RAY DIFFRACTION93
1.6151-1.63820.22441850.19413823X-RAY DIFFRACTION97
1.6382-1.66260.22641910.18593857X-RAY DIFFRACTION99
1.6626-1.68860.21572040.18723868X-RAY DIFFRACTION100
1.6886-1.71630.20221980.17783901X-RAY DIFFRACTION100
1.7163-1.74590.22752040.17453861X-RAY DIFFRACTION100
1.7459-1.77760.19542140.1693865X-RAY DIFFRACTION100
1.7776-1.81180.20111910.17073899X-RAY DIFFRACTION100
1.8118-1.84880.20811940.17093882X-RAY DIFFRACTION100
1.8488-1.8890.20651790.17213889X-RAY DIFFRACTION99
1.889-1.93290.19612170.17213885X-RAY DIFFRACTION100
1.9329-1.98130.20482000.16733892X-RAY DIFFRACTION100
1.9813-2.03480.18251690.16673950X-RAY DIFFRACTION100
2.0348-2.09470.17862330.16343891X-RAY DIFFRACTION100
2.0947-2.16230.18181900.15763952X-RAY DIFFRACTION100
2.1623-2.23960.18432370.15553855X-RAY DIFFRACTION100
2.2396-2.32920.17612180.15333893X-RAY DIFFRACTION100
2.3292-2.43520.16012210.15683897X-RAY DIFFRACTION99
2.4352-2.56360.17872100.16273895X-RAY DIFFRACTION100
2.5636-2.72420.18392070.16633955X-RAY DIFFRACTION100
2.7242-2.93440.20462030.16793978X-RAY DIFFRACTION100
2.9344-3.22960.20511950.16853996X-RAY DIFFRACTION100
3.2296-3.69660.14051920.16373900X-RAY DIFFRACTION97
3.6966-4.65620.20851930.15614035X-RAY DIFFRACTION100
4.6562-39.03010.18212260.17374142X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.1547-0.1923-0.38892.8559-1.66842.03490.06480.31370.1974-0.4946-0.06470.186-0.2884-0.2048-0.01150.23190.0246-0.02730.17060.02030.120710.685812.730112.6163
21.2656-0.119-0.35031.33390.23931.76410.03990.04310.0447-0.1267-0.03350.1599-0.1877-0.2183-0.01050.08670.0099-0.01470.08370.01870.09818.043911.411927.2745
30.8928-0.10360.45891.0468-0.54882.8734-0.0429-0.037-0.03150.11110.0163-0.1558-0.03670.5079-0.03480.0716-0.01540.00070.17120.00340.103128.93096.063338.6415
42.3459-1.34610.17141.737-0.57651.33660.0055-0.09830.18970.2094-0.0030.0473-0.3237-0.03640.0350.1167-0.0060.02480.096-0.01040.103812.914316.922138.0679
51.02010.2198-0.05491.5242-0.1140.9418-0.1408-0.081-0.23610.14610.07620.26010.2728-0.20620.0140.1353-0.04980.04550.15370.03980.18896.4382-3.303237.8709
60.3479-0.18630.070.99050.37121.78510.0578-0.091-0.0725-0.055-0.0085-0.02410.03090.2992-0.05190.0901-0.01240.00710.11320.01290.099920.7791-0.256925.1582
70.73911.15681.11382.08111.85422.09950.02-0.1534-0.07040.17770.214-0.36630.25830.8521-0.1370.19850.08230.00710.3871-0.00760.270433.0206-6.792123.9446
81.3856-0.1951-0.54131.2565-0.16243.0652-0.10990.1402-0.3067-0.0421-0.15390.23090.5898-0.16220.18780.2195-0.04340.01670.079-0.0130.190913.5171-11.488519.2865
90.6798-0.2127-0.37761.1459-0.3861.2413-0.1575-0.51030.08070.33090.2184-0.39180.32210.96580.0490.21690.2016-0.07910.472-0.07410.174436.25914.096168.9767
100.76990.10370.26491.03450.90394.8666-0.05760.12780.1422-0.07450.05290.1288-0.4343-0.5232-0.0580.11070.04080.00580.15170.02470.102717.494813.024554.168
114.0493-0.3882-0.70251.17860.01851.6105-0.10660.04110.0964-0.12020.2131-0.3763-0.03650.4578-0.0770.1251-0.00070.02370.2301-0.07270.174236.04148.084653.7693
126.2727-0.5908-1.0544.36671.58892.2238-0.41260.3296-0.4346-0.09070.1246-0.20810.4890.28980.19430.19340.06080.02140.165-0.00190.099732.3848-1.948152.6698
132.4314-2.1074-0.76343.31030.76620.2478-0.38630.0127-0.42360.39630.18020.24050.56320.15270.01340.53480.08090.11850.2391-0.01730.267521.3478-14.468762.5593
141.1010.1272-0.5110.22620.33232.1841-0.0697-0.0510.1066-0.02430.08920.03150.019-0.13510.02310.29080.18760.08250.1302-0.05060.048719.70125.136269.2258
150.23960.27860.33453.925-2.77593.27660.03170.32380.2861-0.01330.05410.2052-0.2579-0.7765-0.0210.30950.15350.060.38040.04850.26846.91710.601370.927
160.2447-0.0355-0.43390.44820.72751.7322-0.2517-0.1024-0.2205-0.01710.0077-0.07840.70220.240.0410.53630.19190.19120.1242-0.0617-0.004916.9408-6.254878.0803
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 87 through 116 )
2X-RAY DIFFRACTION2chain 'A' and (resid 117 through 199 )
3X-RAY DIFFRACTION3chain 'A' and (resid 200 through 227 )
4X-RAY DIFFRACTION4chain 'A' and (resid 228 through 253 )
5X-RAY DIFFRACTION5chain 'A' and (resid 254 through 302 )
6X-RAY DIFFRACTION6chain 'A' and (resid 303 through 349 )
7X-RAY DIFFRACTION7chain 'A' and (resid 350 through 375 )
8X-RAY DIFFRACTION8chain 'A' and (resid 376 through 411 )
9X-RAY DIFFRACTION9chain 'B' and (resid 89 through 199 )
10X-RAY DIFFRACTION10chain 'B' and (resid 200 through 227 )
11X-RAY DIFFRACTION11chain 'B' and (resid 228 through 253 )
12X-RAY DIFFRACTION12chain 'B' and (resid 254 through 271 )
13X-RAY DIFFRACTION13chain 'B' and (resid 272 through 302 )
14X-RAY DIFFRACTION14chain 'B' and (resid 303 through 349 )
15X-RAY DIFFRACTION15chain 'B' and (resid 350 through 375 )
16X-RAY DIFFRACTION16chain 'B' and (resid 376 through 411 )

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