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

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Basic information

Entry
Database: PDB / ID: 6imt
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 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-AK0 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.483 Å
AuthorsZhang, X.L. / Su, H.X. / Xu, Y.C.
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)81,75818
Polymers80,1932
Non-polymers1,56516
Water7,170398
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1920 Å2
ΔGint-105 kcal/mol
Surface area26610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.125, 80.599, 163.785
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, 414 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-AK0 / (1S)-1-[2-(6-fluoro-1H-indol-3-yl)ethyl]-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde


Mass: 382.428 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23FN2O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 398 / 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: 48.58 %
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 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: 1.483→30.914 Å / Num. obs: 127958 / % possible obs: 97.1 % / Redundancy: 12.7 % / CC1/2: 0.8 / Net I/σ(I): 10.2
Reflection shellResolution: 1.483→1.5 Å

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementResolution: 1.483→30.914 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1959 6234 5.02 %
Rwork0.1785 --
obs0.1794 124216 97.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.483→30.914 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5111 0 100 398 5609
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0055310
X-RAY DIFFRACTIONf_angle_d0.7567207
X-RAY DIFFRACTIONf_dihedral_angle_d15.1221945
X-RAY DIFFRACTIONf_chiral_restr0.065824
X-RAY DIFFRACTIONf_plane_restr0.005922
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4833-1.50010.22041300.21332338X-RAY DIFFRACTION59
1.5001-1.51780.23211570.20763046X-RAY DIFFRACTION76
1.5178-1.53630.25431900.20863495X-RAY DIFFRACTION87
1.5363-1.55570.23011920.20353797X-RAY DIFFRACTION94
1.5557-1.57620.20822140.19843888X-RAY DIFFRACTION97
1.5762-1.59780.22651920.18733969X-RAY DIFFRACTION99
1.5978-1.62060.18572030.18264025X-RAY DIFFRACTION100
1.6206-1.64480.19671700.18244049X-RAY DIFFRACTION100
1.6448-1.67050.19322180.17893969X-RAY DIFFRACTION100
1.6705-1.69790.18862230.18214004X-RAY DIFFRACTION100
1.6979-1.72720.20412110.18344042X-RAY DIFFRACTION100
1.7272-1.75860.20662070.17394032X-RAY DIFFRACTION100
1.7586-1.79240.19942000.17634024X-RAY DIFFRACTION100
1.7924-1.8290.1972340.17764004X-RAY DIFFRACTION100
1.829-1.86870.20932110.18354040X-RAY DIFFRACTION100
1.8687-1.91220.19722050.18114016X-RAY DIFFRACTION100
1.9122-1.960.18932090.18534024X-RAY DIFFRACTION100
1.96-2.0130.20672280.17454043X-RAY DIFFRACTION100
2.013-2.07220.18112140.16924047X-RAY DIFFRACTION100
2.0722-2.13910.19221910.17164036X-RAY DIFFRACTION100
2.1391-2.21550.17962360.16684030X-RAY DIFFRACTION100
2.2155-2.30420.18962280.16774052X-RAY DIFFRACTION100
2.3042-2.4090.18412280.17154037X-RAY DIFFRACTION100
2.409-2.5360.17692230.17464049X-RAY DIFFRACTION100
2.536-2.69480.21442100.17844091X-RAY DIFFRACTION100
2.6948-2.90270.19652020.18324122X-RAY DIFFRACTION100
2.9027-3.19450.18922070.18574097X-RAY DIFFRACTION100
3.1945-3.65610.1972250.17774130X-RAY DIFFRACTION100
3.6561-4.60390.18882270.16894143X-RAY DIFFRACTION100
4.6039-30.92080.2012490.18264343X-RAY DIFFRACTION100
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)
13.5010.85220.02073.2836-1.40873.15420.00180.36270.2014-0.5115-0.06780.1835-0.3027-0.13350.03630.20770.023-0.01890.16050.00580.107969.082392.609213.3153
21.1459-0.1232-0.36571.30670.33151.54440.03340.0850.0638-0.1323-0.04420.1686-0.1914-0.19560.00420.09070.0098-0.00780.07960.01150.101166.227792.027927.4015
31.0541-0.45060.46811.0126-0.12683.0154-0.0322-0.0735-0.01340.05890.0604-0.13840.00920.4627-0.04180.0696-0.01760.00790.1460.00030.10487.074286.571538.8484
41.923-0.98230.06651.4191-0.42391.0331-0.0174-0.09630.19580.19570.00070.0349-0.2732-0.01820.02380.1227-0.00560.02340.0904-0.01270.112371.090497.452838.2485
54.989-2.2096-1.48513.71460.76922.4955-0.1316-0.1783-0.10970.22980.03130.21670.0016-0.16170.11620.0648-0.01560.0130.09110.02030.081865.883688.375341.682
60.54410.1852-0.57760.8121-0.10141.3782-0.076-0.0453-0.20010.1199-0.01840.25050.3019-0.19810.00730.16-0.05110.05360.12910.0150.220665.350273.649833.4768
73.13730.48082.03281.22910.4222.3895-0.02380.0101-0.0509-0.15740.084-0.2165-0.15650.4902-0.02660.1119-0.01870.0520.195-0.00870.120788.149582.167620.7633
81.63951.27451.18672.03761.13331.2510.0134-0.0921-0.15960.02920.1293-0.38680.21540.5493-0.1020.1390.05120.03020.2787-0.00470.223191.096973.640124.0155
92.040.5801-0.53321.03830.09662.3542-0.11170.0902-0.28480.0231-0.1430.28790.463-0.40030.14460.203-0.09350.08380.1192-0.04290.240766.201569.533525.3023
101.3518-0.5648-0.13672.07550.01323.2062-0.05860.1803-0.3343-0.1158-0.20470.14120.4603-0.03940.21690.2136-0.01210.02470.0866-0.01940.164675.810568.669113.7092
110.4060.89340.05193.2175-0.27341.2457-0.0265-0.46130.03510.4818-0.001-0.3845-0.00040.60260.05010.34580.1391-0.10910.5564-0.10810.211393.542288.105379.2282
121.02280.1185-0.45940.6758-0.15731.0396-0.2138-0.3789-0.05070.21360.2733-0.32150.37480.7710.00990.22930.2083-0.02970.3659-0.06030.186494.04283.64966.092
130.51650.22620.40880.71460.83764.0223-0.05810.08050.1261-0.04010.10060.0888-0.3953-0.6186-0.07270.11540.05320.01280.1860.02920.107275.582993.545154.356
143.4841-0.2755-0.53560.9294-0.04881.4423-0.07710.03710.1224-0.07780.2043-0.35780.00610.4173-0.07450.11890.01060.01670.2132-0.07350.184694.085588.525454.1252
155.9657-0.1811-0.472.94441.32581.9682-0.31570.391-0.5218-0.01180.075-0.14460.46370.23180.18170.20120.06190.02530.1516-0.01390.124890.414678.4352.9148
161.8425-1.6807-0.77352.3650.7680.3296-0.37490.0632-0.3910.38660.15660.24740.48240.06550.14640.49620.0440.11820.2291-0.00730.251478.200267.273761.9257
171.1614-0.3215-0.36891.04740.98351.4424-0.2519-0.0261-0.2180.01820.097-0.05590.37430.09030.02420.45690.19090.12890.0513-0.06710.09882.350375.043865.3982
182.0373-0.316-0.95851.77670.01922.51660.14310.02120.28350.1070.09050.0955-0.4828-0.2475-0.01830.31210.18780.0710.1927-0.02030.142873.652494.503273.1858
190.2192-0.05050.20261.6691-0.99892.7230.06440.36290.21730.05950.03540.2082-0.2056-0.7179-0.0590.29570.15040.0610.37580.04720.225765.048291.008671.3942
200.2765-0.0144-0.44170.27030.5821.8051-0.3178-0.084-0.3084-0.07610.0259-0.10440.81410.22730.0970.60570.17780.1960.1129-0.0430.074974.704274.16578.3044
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 88 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 271 )
6X-RAY DIFFRACTION6chain 'A' and (resid 272 through 325 )
7X-RAY DIFFRACTION7chain 'A' and (resid 326 through 349 )
8X-RAY DIFFRACTION8chain 'A' and (resid 350 through 375 )
9X-RAY DIFFRACTION9chain 'A' and (resid 376 through 392 )
10X-RAY DIFFRACTION10chain 'A' and (resid 393 through 411 )
11X-RAY DIFFRACTION11chain 'B' and (resid 89 through 116 )
12X-RAY DIFFRACTION12chain 'B' and (resid 117 through 199 )
13X-RAY DIFFRACTION13chain 'B' and (resid 200 through 227 )
14X-RAY DIFFRACTION14chain 'B' and (resid 228 through 253 )
15X-RAY DIFFRACTION15chain 'B' and (resid 254 through 271 )
16X-RAY DIFFRACTION16chain 'B' and (resid 272 through 302 )
17X-RAY DIFFRACTION17chain 'B' and (resid 303 through 325 )
18X-RAY DIFFRACTION18chain 'B' and (resid 326 through 349 )
19X-RAY DIFFRACTION19chain 'B' and (resid 350 through 375 )
20X-RAY DIFFRACTION20chain 'B' and (resid 376 through 411 )

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