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

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Basic information

Entry
Database: PDB / ID: 6inm
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 / 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) / 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: 1.999 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 26, 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)81,1639
Polymers80,1932
Non-polymers9707
Water4,414245
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2170 Å2
ΔGint-102 kcal/mol
Surface area26090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.122, 80.104, 163.259
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) / Strain (production host): BL21(DE3)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 252 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: isolated from a natural source / Formula: C22H24N2O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 245 / 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: 2.37 Å3/Da / Density % sol: 48.09 %
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: BL17U1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 14, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.999→45.014 Å / Num. obs: 99243 / % possible obs: 99.9 % / Redundancy: 3.827 % / Biso Wilson estimate: 27.85 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.066 / Rrim(I) all: 0.077 / Χ2: 1.006 / Net I/σ(I): 17.27 / Num. measured all: 293702 / Scaling rejects: 12
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
2.18-2.243.8090.4583.3521808573257250.8540.53399.9
2.24-2.33.8150.3893.9621151554955440.8990.45299.9
2.3-2.363.820.3294.6620455536153550.9310.38399.9
2.36-2.443.820.2725.5120036524852450.9520.31799.9
2.44-2.523.8260.2446.1219442508450810.960.28499.9
2.52-2.613.8220.2117.0318633488248750.9670.24599.9
2.61-2.73.8140.1748.2817899470046930.9760.20399.9
2.7-2.813.8350.14110.0817517457645680.9820.16499.8
2.81-2.943.8150.11911.8816704438743790.9890.13999.8
2.94-3.083.840.09114.7116085419941890.9940.10699.8
3.08-3.253.8060.0718.4714973393639340.9950.08299.9
3.25-3.453.7860.05323.5314219375937560.9980.06199.9
3.45-3.683.7280.04327.7213128352735210.9980.05199.8
3.68-3.983.710.03434.6612145328832740.9990.03999.6
3.98-4.363.9170.02742.511822301930180.9990.031100
4.36-4.873.9290.02346.6510739273327330.9990.027100
4.87-5.633.9390.02642.639502241224120.9990.03100
5.63-6.893.9440.02542.457963201920190.9990.029100
6.89-9.753.9380.01759.116234158615830.9990.0299.8
9.75-45.0143.8840.01567.9432478568360.9990.01797.7

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.999→45.014 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.16 / Phase error: 22.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2244 4967 5 %
Rwork0.1886 94276 -
obs0.1905 99243 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.81 Å2 / Biso mean: 38.8338 Å2 / Biso min: 13.11 Å2
Refinement stepCycle: final / Resolution: 1.999→45.014 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5091 0 62 245 5398
Biso mean--65.56 39.74 -
Num. residues----641
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075260
X-RAY DIFFRACTIONf_angle_d0.7287163
X-RAY DIFFRACTIONf_chiral_restr0.044829
X-RAY DIFFRACTIONf_plane_restr0.005919
X-RAY DIFFRACTIONf_dihedral_angle_d2.9973164
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 (%)
1.9989-2.02160.30081500.29872928307893
2.0216-2.04540.27391690.267831383307100
2.0454-2.07030.29681670.2631543321100
2.0703-2.09650.23331680.248431363304100
2.0965-2.12410.28931580.241331163274100
2.1241-2.15320.2731710.222432613432100
2.1532-2.1840.23611630.224630613224100
2.184-2.21660.26371690.216231803349100
2.2166-2.25120.27511680.214931663334100
2.2512-2.28810.24921620.209331083270100
2.2881-2.32760.24411700.210531633333100
2.3276-2.36990.24061670.205431583325100
2.3699-2.41550.26861660.199431853351100
2.4155-2.46480.23821570.201530893246100
2.4648-2.51840.20521700.203832123382100
2.5184-2.57690.25371600.184231173277100
2.5769-2.64140.24681670.184731503317100
2.6414-2.71280.21651600.177931683328100
2.7128-2.79260.22281660.173931373303100
2.7926-2.88270.20261660.184331703336100
2.8827-2.98570.25741700.1931613331100
2.9857-3.10520.25791670.18831163283100
3.1052-3.24650.24551680.180731503318100
3.2465-3.41760.20031700.175331853355100
3.4176-3.63170.19941620.178731573319100
3.6317-3.91190.20861640.173531013265100
3.9119-4.30530.1941640.15831593323100
4.3053-4.92760.18651660.158831713337100
4.9276-6.20570.23051720.200831473319100
6.2057-45.02580.19661700.1743132330299
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)
11.6056-0.4265-0.21371.8690.28672.42540.05480.16630.1071-0.2165-0.02580.2173-0.2507-0.2123-0.03750.18980.0237-0.00580.15940.03470.19498.712191.505923.8362
23.3146-0.6979-0.63572.2788-1.10494.736-0.117-0.16630.11430.20.0099-0.33190.02240.73590.09430.2014-0.0114-0.00060.2708-0.00440.251528.845886.036338.7343
32.9408-1.1686-0.06552.7097-0.27982.05110.0045-0.26510.06230.21340.01740.0945-0.2046-0.1524-0.02470.2089-0.00850.03680.23750.00410.187610.551493.192439.5327
41.1155-0.123-0.39181.360.21392.2923-0.0896-0.1236-0.23480.15160.08790.45740.4681-0.3391-0.0070.2352-0.05620.04470.20640.05360.32637.270973.034333.4032
55.5952-0.51312.18022.432-0.12663.43060.0192-0.18050.159-0.1753-0.05-0.3745-0.12590.87340.02720.22-0.02720.09330.39080.01310.264630.639282.006921.3954
62.65470.7352.42272.38262.11554.2687-0.0870.1412-0.20170.21360.3198-0.33170.32381.0731-0.29060.3150.10490.02440.4542-0.01190.355832.391472.569123.2264
72.2759-0.4839-1.23492.1794-0.63874.9964-0.04350.1463-0.3806-0.1193-0.19770.23160.7966-0.15240.28160.3936-0.03740.01270.1758-0.00360.313112.905968.578219.3951
81.13870.98390.14513.7627-1.42652.2542-0.0213-0.77180.07380.2717-0.0632-0.53210.31641.63510.10730.56650.269-0.09751.0825-0.19290.404135.223487.317678.7541
91.0631-0.2416-0.96420.60180.41530.9178-0.0316-0.4493-0.22240.3935-0.0152-0.51940.93961.2935-0.28840.34790.4931-0.26351.3189-0.17430.434542.833381.613166.9827
101.98450.1371-1.12291.1199-0.03851.8585-0.3914-0.56470.01390.23720.5002-0.35320.55551.2957-0.08220.42460.2426-0.02820.5868-0.10560.284533.135683.747865.5416
113.0218-1.00951.36272.41770.78325.0768-0.12610.09330.1907-0.10920.09450.1272-0.5355-0.53460.05350.22260.03040.03420.24450.02230.196417.372192.957954.1358
124.3218-1.0489-1.24562.2052-0.22690.8253-0.28710.25310.0999-0.25270.4476-0.5686-0.08880.9048-0.2050.24710.00990.04170.5578-0.15250.335335.880788.011853.898
132.2097-1.9238-2.28944.39040.57813.3998-0.7470.1292-0.2342-0.05590.2524-0.33591.00010.52570.46270.34360.09770.020.3551-0.05410.251732.261378.003952.7824
141.5647-1.09740.27041.7497-0.44950.1567-0.64810.113-0.48360.27650.41550.05891.2287-0.0190.09090.92510.18320.19920.2911-0.02620.408620.181766.635861.7986
153.0747-0.1898-1.40531.036-0.28243.01770.0466-0.18280.1999-0.1020.0083-0.022-0.04090.0121-0.05180.5010.13680.00770.2971-0.01830.21519.353385.346869.3069
161.01730.18880.66462.9958-2.5792.91710.20750.45480.374-0.1614-0.0720.3115-0.5156-1.1325-0.1680.65660.23480.02930.5430.07530.36996.771490.45971.0763
170.108-0.1417-0.19691.65960.85050.6141-0.4657-0.4929-0.33450.25970.1753-0.05531.77180.29360.17960.98420.30320.10140.26680.04420.2916.48873.73478.0783
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 88 through 199 )A88 - 199
2X-RAY DIFFRACTION2chain 'A' and (resid 200 through 227 )A200 - 227
3X-RAY DIFFRACTION3chain 'A' and (resid 228 through 271 )A228 - 271
4X-RAY DIFFRACTION4chain 'A' and (resid 272 through 325 )A272 - 325
5X-RAY DIFFRACTION5chain 'A' and (resid 326 through 350 )A326 - 350
6X-RAY DIFFRACTION6chain 'A' and (resid 351 through 375 )A351 - 375
7X-RAY DIFFRACTION7chain 'A' and (resid 376 through 410 )A376 - 410
8X-RAY DIFFRACTION8chain 'B' and (resid 91 through 116 )B91 - 116
9X-RAY DIFFRACTION9chain 'B' and (resid 117 through 138 )B117 - 138
10X-RAY DIFFRACTION10chain 'B' and (resid 139 through 199 )B139 - 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 349 )B303 - 349
16X-RAY DIFFRACTION16chain 'B' and (resid 350 through 375 )B350 - 375
17X-RAY DIFFRACTION17chain 'B' and (resid 376 through 411 )B376 - 411

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