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

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Basic information

Entry
Database: PDB / ID: 6ink
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 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 / calcium channel complex / cellular response to epinephrine stimulus / 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) / 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-AKU / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsZhang, X.L. / Su, H.X. / Xu, Y.C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China 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 25, 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)81,34912
Polymers80,1932
Non-polymers1,15710
Water4,648258
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1380 Å2
ΔGint-5 kcal/mol
Surface area26420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.817, 80.276, 163.321
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) / Variant (production host): BL21(DE3)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 268 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-AKU / (1S)-1-[2-(1H-indol-3-yl)ethyl]-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde


Mass: 364.438 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24N2O3
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 258 / 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: 2.36 Å3/Da / Density % sol: 47.95 %
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: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 20, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.7→46.915 Å / Num. obs: 160357 / % possible obs: 99.7 % / Redundancy: 3.506 % / Biso Wilson estimate: 24.99 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.045 / Rrim(I) all: 0.053 / Χ2: 1.037 / Net I/σ(I): 18.61 / Num. measured all: 404568
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.9-1.953.5940.4433.1330790857785660.8710.52299.9
1.95-23.5670.3513.9429712834183300.9020.41499.9
2-2.063.5560.2685.0629043817881680.9380.31699.9
2.06-2.123.5440.2086.3727666781978060.9620.24599.8
2.12-2.193.530.1588.2727019766476550.9770.18799.9
2.19-2.273.4960.1319.6825685736373480.9810.15699.8
2.27-2.363.30.10211.5423654718971670.9880.12299.7
2.36-2.453.2590.08213.8122009678967540.9920.09899.5
2.45-2.563.6730.07316.3424242660466000.9950.08599.9
2.56-2.693.6650.06219.1423063629562920.9960.073100
2.69-2.833.6130.0522.5321526596859580.9970.05899.8
2.83-33.570.04325.7220126564656370.9980.0599.8
3-3.213.4730.03629.8818545536253390.9980.04399.6
3.21-3.473.0860.02933.6314985492448560.9990.03598.6
3.47-3.83.5380.02640.7916076457345440.9990.03199.4
3.8-4.253.6050.02345.4914686408440740.9990.02799.8
4.25-4.913.5730.02248.0112947363236240.9990.02699.8
4.91-6.013.3960.02343.310315305830370.9990.02899.3
6.01-8.53.290.02246.377683237023350.9990.02698.5
8.5-46.9153.7120.0255.224796130112920.9990.02499.3

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Processing

Software
NameClassification
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→46.915 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.15 / Phase error: 22.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2115 8026 5.01 %
Rwork0.1847 152331 -
obs0.186 160357 99.32 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 106.61 Å2 / Biso mean: 39.1268 Å2 / Biso min: 14.63 Å2
Refinement stepCycle: final / Resolution: 1.7→46.915 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5084 0 74 258 5416
Biso mean--46.55 40.94 -
Num. residues----641
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095262
X-RAY DIFFRACTIONf_angle_d0.8817160
X-RAY DIFFRACTIONf_chiral_restr0.055829
X-RAY DIFFRACTIONf_plane_restr0.006917
X-RAY DIFFRACTIONf_dihedral_angle_d4.4243162
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 (%)
1.7002-1.71950.38632320.3474509474190
1.7195-1.73970.36262710.314551345405100
1.7397-1.76090.34142700.308851205390100
1.7609-1.78320.30672710.289250695340100
1.7832-1.80670.30142650.28015125539099
1.8067-1.83140.29052710.273950715342100
1.8314-1.85760.30342680.26345068533699
1.8576-1.88530.29252660.24845005527199
1.8853-1.91480.26332700.242951565426100
1.9148-1.94620.26592680.234350885356100
1.9462-1.97970.2542740.229351735447100
1.9797-2.01570.23482640.217450835347100
2.0157-2.05450.21572680.190551165384100
2.0545-2.09640.23122700.189450645334100
2.0964-2.1420.22962670.184351445411100
2.142-2.19190.20192650.17850825347100
2.1919-2.24670.21042760.17551775453100
2.2467-2.30740.21512690.180450895358100
2.3074-2.37530.20532670.175850075274100
2.3753-2.4520.22472690.171650925361100
2.452-2.53960.20872720.171751475419100
2.5396-2.64130.21292660.170850775343100
2.6413-2.76150.19232710.168251865457100
2.7615-2.9070.22652670.172750575324100
2.907-3.08910.19992710.172151125383100
3.0891-3.32760.19082650.16965065533099
3.3276-3.66240.19052690.17085058532799
3.6624-4.1920.1942650.166150785343100
4.192-5.28040.17842710.160751185389100
5.2804-46.93330.182680.17995061532999
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)
14.71561.03650.37245.0351-2.44733.80310.26470.41220.3895-0.688-0.2010.2832-0.532-0.3309-0.06220.44060.12460.00260.34550.02260.219410.717192.279413.5606
21.372-0.7216-0.52532.5191.07272.80970.14260.13610.1253-0.3026-0.15860.2387-0.4745-0.46420.00230.21020.0790.00470.21250.0210.1888.176491.580727.3764
33.6009-0.83660.42141.3679-0.98996.5881-0.0907-0.0992-0.04340.09030.0824-0.2545-0.09250.67450.0210.1719-0.02940.02160.2099-0.02850.240228.939186.149938.9526
44.3679-1.91730.10763.2201-0.00862.37230.1715-0.03180.3504-0.0119-0.1189-0.0476-0.5081-0.1861-0.0370.24440.0120.06470.1754-0.0230.184212.904197.095638.1956
58.5484-5.3129-2.11123.63591.90865.2182-0.2331-0.0876-0.09820.32990.00830.2348-0.1065-0.4980.25320.1793-0.01220.04830.24650.02270.22277.421588.121441.8842
64.41371.2112-0.35862.71760.04841.3606-0.0965-0.0237-0.13660.3244-0.02010.56020.4549-0.57780.08950.3299-0.12210.11760.372-0.0050.37945.337969.888435.4406
71.2356-0.56350.09771.63350.4642.52650.0434-0.0686-0.0421-0.1609-0.0354-0.09710.07020.2629-0.01780.1483-0.0130.02840.14350.00860.179221.113679.964825.2716
83.90941.15022.22062.14511.66263.5819-0.05170.1049-0.0857-0.01190.2726-0.4650.33470.9589-0.20910.25760.08230.05650.414-0.01820.34733.085373.303423.9314
92.0667-0.0645-0.85412.1972-0.64155.0359-0.12360.243-0.3082-0.1617-0.22640.29120.8216-0.59030.33770.3197-0.07860.03870.1967-0.05870.273712.972168.867419.2271
101.3969-0.0269-0.94770.7535-0.27151.4622-0.4637-0.99510.09920.39770.5043-0.4490.54521.64690.03180.4440.4005-0.09770.9041-0.11840.364135.344484.163469.3913
113.9592-0.76390.623.31531.43657.6631-0.02940.06180.2435-0.1350.07660.0943-0.3528-0.5823-0.02630.17850.03470.01880.19160.01680.204717.263293.036354.3638
126.7249-0.8103-0.76192.2868-0.6521.2674-0.1709-0.17540.4545-0.10970.2881-0.62610.15530.8268-0.07420.23950.05950.02460.461-0.13080.338835.861488.131154.371
132.8851-3.8776-1.51996.0452.23991.4101-0.47370.279-0.3366-0.01720.1442-0.33751.05530.56730.3160.42150.16190.04630.3583-0.0280.263332.252278.026353.1071
140.09390.1894-0.06050.4628-0.09580.0041-0.58680.15-0.53660.26020.27390.11111.1167-0.00260.13441.0880.14210.27360.3013-0.02750.465119.913666.717961.7857
152.8026-0.786-2.2470.8090.6052.941-0.0383-0.08610.1796-0.19970.0229-0.17780.4093-0.07080.01030.54230.1710.0240.286-0.0240.231918.538685.741968.9789
161.6599-1.85852.13575.8913-2.94033.92010.02620.51620.3090.34020.04120.1816-0.0486-1.0178-0.0940.43890.17930.08750.53210.06590.30496.191489.510171.8635
170.9805-0.55470.49251.58350.65531.1635-0.5996-0.6585-0.48010.01040.1570.04321.84240.32530.2461.12840.32570.22770.18020.12970.324315.987373.58878.1154
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 88 through 116 )A88 - 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 302 )A272 - 302
7X-RAY DIFFRACTION7chain 'A' and (resid 303 through 349 )A303 - 349
8X-RAY DIFFRACTION8chain 'A' and (resid 350 through 375 )A350 - 375
9X-RAY DIFFRACTION9chain 'A' and (resid 376 through 410 )A376 - 410
10X-RAY DIFFRACTION10chain 'B' and (resid 91 through 199 )B91 - 199
11X-RAY DIFFRACTION11chain 'B' and (resid 200 through 227 )B200 - 227
12X-RAY DIFFRACTION12chain 'B' and (resid 228 through 253 )B228 - 253
13X-RAY DIFFRACTION13chain 'B' and (resid 254 through 271 )B254 - 271
14X-RAY DIFFRACTION14chain 'B' and (resid 272 through 302 )B272 - 302
15X-RAY DIFFRACTION15chain 'B' and (resid 303 through 350 )B303 - 350
16X-RAY DIFFRACTION16chain 'B' and (resid 351 through 375 )B351 - 375
17X-RAY DIFFRACTION17chain 'B' and (resid 376 through 411 )B376 - 411

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