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- PDB-7cbj: Crystal structure of PDE4D catalytic domain in complex with compo... -

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Basic information

Entry
Database: PDB / ID: 7cbj
TitleCrystal structure of PDE4D catalytic domain in complex with compound 36
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4D / inhibitor / Complex structure / METAL BINDING PROTEIN
Function / homology
Function and homology information


signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / regulation of cardiac muscle cell contraction / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / regulation of cardiac muscle cell contraction / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of heart rate / heterocyclic compound binding / adrenergic receptor signaling pathway / voltage-gated calcium channel complex / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / calcium channel regulator activity / cAMP-mediated signaling / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / DARPP-32 events / negative regulation of peptidyl-serine phosphorylation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cAMP binding / cellular response to cAMP / cellular response to epinephrine stimulus / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / positive regulation of type II interferon production / ATPase binding / T cell receptor signaling pathway / G alpha (s) signalling events / scaffold protein binding / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / signal transduction / membrane / metal ion binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / 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.
Similarity search - Domain/homology
Chem-FTX / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.5 Å
AuthorsZhang, X.L. / Xu, Y.C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21877122 China
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment.
Authors: Zhang, R. / Li, H. / Zhang, X. / Li, J. / Su, H. / Lu, Q. / Dong, G. / Dou, H. / Fan, C. / Gu, Z. / Mu, Q. / Tang, W. / Xu, Y. / Liu, H.
History
DepositionJun 12, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)81,88720
Polymers80,1932
Non-polymers1,69418
Water5,873326
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4550 Å2
ΔGint-67 kcal/mol
Surface area27220 Å2
Unit cell
Length a, b, c (Å)58.124, 80.463, 164.096
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 344 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-FTX / (1S)-1-[(7-chloranyl-1H-indol-3-yl)methyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbaldehyde


Mass: 384.856 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21ClN2O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 48.59 %
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: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 23, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.5→35 Å / Num. obs: 121538 / % possible obs: 98.6 % / Redundancy: 11.1 % / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.033 / Rrim(I) all: 0.114 / Χ2: 0.905 / Net I/σ(I): 7.6 / Num. measured all: 1345876
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.5-1.5510.11.606117860.6980.5051.6860.75297.1
1.55-1.6210.71.189119000.8350.3631.2440.78297.6
1.62-1.6910.30.848119260.8870.2660.890.83997.9
1.69-1.7811.10.585119950.9380.1750.6110.99598.3
1.78-1.8911.20.404120420.9640.1210.4221.15898.5
1.89-2.0410.60.243121530.9790.0760.2551.19898.9
2.04-2.2411.70.136121750.990.040.1420.89799
2.24-2.5611.30.098122630.9940.030.1030.78599.3
2.56-3.2311.90.08124560.9950.0240.0840.72699.7
3.23-3511.50.087128420.9930.0260.0910.9299.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.17 Å33.52 Å
Translation5.17 Å33.52 Å

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHASER2.8.2phasing
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6INK

6ink


Resolution: 1.5→33.52 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 20.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2054 5540 4.94 %
Rwork0.1812 106677 -
obs0.1823 112217 91.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 78.55 Å2 / Biso mean: 22.3094 Å2 / Biso min: 1.71 Å2
Refinement stepCycle: final / Resolution: 1.5→33.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5204 0 106 326 5636
Biso mean--33.28 28.59 -
Num. residues----649
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5-1.520.2668160.254841443011
1.52-1.540.2857580.25171052111027
1.54-1.560.2356950.25691959205451
1.56-1.580.25721690.24313015318478
1.58-1.60.2811960.22013558375493
1.6-1.620.25321850.20413705389095
1.62-1.640.21981760.19993779395597
1.64-1.670.24061890.1973790397998
1.67-1.690.22541990.19763766396598
1.69-1.720.21182010.19223793399498
1.72-1.750.2322040.18563821402598
1.75-1.780.18932060.18163763396998
1.78-1.820.21231820.18393860404298
1.82-1.850.2051860.19273794398099
1.85-1.890.22571920.19613838403099
1.89-1.940.23562130.23865407899
1.94-1.980.22011940.19923827402199
1.98-2.040.19381670.1793862402999
2.04-2.10.18252260.17663844407099
2.1-2.170.20011930.17053885407899
2.17-2.240.19282240.16933822404699
2.24-2.330.21562220.17473851407399
2.33-2.440.1862210.17443893411499
2.44-2.570.21332130.176738694082100
2.57-2.730.1831980.177739404138100
2.73-2.940.22012010.180739334134100
2.94-3.230.21441920.185339974189100
3.24-3.70.17512000.175139614161100
3.7-4.660.21911920.157240344226100
4.66-33.520.17852300.178941874417100
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)
14.09550.3345-0.14083.8042-1.36783.36930.01430.51430.3318-0.5646-0.04580.2412-0.3801-0.16110.00850.23420.0274-0.02610.18050.02520.12110.716112.867712.7219
20.9420.1914-0.18791.10390.15981.33310.0490.10610.0583-0.1562-0.04550.2155-0.2171-0.2385-0.02150.06680.0060.00140.08120.01110.12128.105411.525127.4037
31.5612-0.5182-0.58560.5805-0.23811.5513-0.0486-0.089-0.02190.07880.0609-0.1862-0.01190.48760.00930.0462-0.01730.00460.1462-0.00160.102528.80426.095839.0917
42.3012-1.21620.00821.40280.0590.97020.0248-0.0730.23970.1079-0.02860.0318-0.2846-0.04320.00470.09380.00530.03080.0727-0.00180.100712.921616.843338.2913
55.2001-2.1152-0.90393.5440.7071.777-0.1207-0.1637-0.03310.19150.03160.1412-0.0004-0.21760.0350.0206-0.01910.03260.10550.04140.09277.79167.734541.6823
60.56940.1493-0.20980.5466-0.26050.9332-0.0521-0.0709-0.1790.09830.00640.29980.31-0.2330.02140.1413-0.06270.05940.12070.02680.227.2481-6.963833.4996
73.8656-0.33451.65371.3456-0.18081.49290.0277-0.13130.0495-0.12530.0288-0.2565-0.06870.4664-0.00260.0927-0.01510.05730.1966-0.0110.122129.82031.646620.591
83.20061.61751.45821.49551.07682.1819-0.0027-0.1761-0.18360.04620.1736-0.48510.16360.6992-0.15270.17140.06520.0370.31970.00430.319633.015-6.975724.0757
91.82260.6081-0.61761.2753-0.9712.6524-0.12210.1227-0.2455-0.0732-0.12210.22140.5005-0.19890.17550.1844-0.05130.03340.0737-0.0330.189413.309-11.548819.0689
100.00060.0649-0.03442.6159-1.12431.4259-0.0109-0.15330.00980.4066-0.0471-0.3765-0.09190.59210.09140.34040.1711-0.1480.6233-0.14810.216236.16017.520579.5864
110.25680.1364-0.2230.87720.18410.3196-0.1533-0.2931-0.07530.18380.2156-0.4360.45450.7799-0.03460.11890.34770.03390.3063-0.12540.17235.95252.837866.2839
121.5082-0.2661-0.32750.4150.83841.7368-0.04920.11210.1512-0.01680.09440.0787-0.3219-0.4968-0.01740.10250.05630.01080.16450.0260.102117.50712.937954.2543
133.981-0.681-0.5870.8433-0.58930.75070.0890.08660.226-0.09150.0749-0.4417-0.01950.4378-0.10720.10820.01280.02230.2649-0.09480.218636.11738.147254.1787
147.6308-2.7147-1.72444.59541.35962.2247-0.2290.3206-0.4097-0.13340.0193-0.21320.42320.32380.19320.18490.07090.02050.1706-0.0240.118732.5984-2.305252.8432
152.776-2.2586-0.11794.5937-0.04440.0112-0.3613-0.1324-0.56720.31390.18330.2880.56080.12930.10940.58870.08290.15710.2240.00140.266920.8737-14.65662.8344
160.6999-0.1103-0.33640.63690.56161.2138-0.1484-0.0137-0.1618-0.06620.0374-0.06390.19160.03940.03770.43170.23290.14230.0715-0.05680.07324.1904-5.522765.5255
171.464-0.6609-0.19531.11210.13940.90520.17720.15810.2945-0.1018-0.03030.026-0.3-0.19560.01550.31940.2770.09590.2108-0.04140.155514.776514.782172.1331
180.8386-0.6060.53944.786-2.72331.75990.13250.42430.317-0.1892-0.02220.4264-0.1579-0.6458-0.10810.35250.16380.04210.35950.0350.26536.55039.696572.0038
190.0663-0.0585-0.16290.61180.49140.7633-0.191-0.0282-0.2064-0.1673-0.0642-0.10240.54120.17910.00320.58260.23270.2070.0795-0.07550.042716.5611-6.4378.4501
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 86 through 116 )A86 - 116
2X-RAY DIFFRACTION2chain 'A' and (resid 117 through 199 )A117 - 199
3X-RAY DIFFRACTION3chain 'A' and (resid 200 through 227 )A200 - 227
4X-RAY DIFFRACTION4chain 'A' and (resid 228 through 253 )A228 - 253
5X-RAY DIFFRACTION5chain 'A' and (resid 254 through 271 )A254 - 271
6X-RAY DIFFRACTION6chain 'A' and (resid 272 through 325 )A272 - 325
7X-RAY DIFFRACTION7chain 'A' and (resid 326 through 349 )A326 - 349
8X-RAY DIFFRACTION8chain 'A' and (resid 350 through 375 )A350 - 375
9X-RAY DIFFRACTION9chain 'A' and (resid 376 through 411 )A376 - 411
10X-RAY DIFFRACTION10chain 'B' and (resid 89 through 116 )B89 - 116
11X-RAY DIFFRACTION11chain 'B' and (resid 117 through 199 )B117 - 199
12X-RAY DIFFRACTION12chain 'B' and (resid 200 through 227 )B200 - 227
13X-RAY DIFFRACTION13chain 'B' and (resid 228 through 253 )B228 - 253
14X-RAY DIFFRACTION14chain 'B' and (resid 254 through 271 )B254 - 271
15X-RAY DIFFRACTION15chain 'B' and (resid 272 through 302 )B272 - 302
16X-RAY DIFFRACTION16chain 'B' and (resid 303 through 325 )B303 - 325
17X-RAY DIFFRACTION17chain 'B' and (resid 326 through 350 )B326 - 350
18X-RAY DIFFRACTION18chain 'B' and (resid 351 through 375 )B351 - 375
19X-RAY DIFFRACTION19chain 'B' and (resid 376 through 411 )B376 - 411

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