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- PDB-7abe: Crystal structure of human phosphodiesterase 4D2 catalytic domain... -

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Basic information

Entry
Database: PDB / ID: 7abe
TitleCrystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-769
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / Phosphodiesterase / cAMP hydrolysis / alternative splicing
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-J2E / DI(HYDROXYETHYL)ETHER / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsSingh, A.K. / Blaazer, A.R. / Zara, L. / de Esch, I.J.P. / Leurs, R. / Brown, D.G.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Union (EU)602666European Union
CitationJournal: To be published
Title: hPDE4D2 structure with inhibitor NPD-769
Authors: Singh, A.K. / Brown, D.G.
History
DepositionSep 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / diffrn_source / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _diffrn_source.pdbx_synchrotron_site / _struct_ncs_dom_lim.beg_auth_comp_id ..._diffrn_source.pdbx_synchrotron_site / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_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
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,84975
Polymers167,2334
Non-polymers6,61671
Water13,727762
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,71424
Polymers41,8081
Non-polymers1,90623
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,42616
Polymers41,8081
Non-polymers1,61815
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,15515
Polymers41,8081
Non-polymers1,34714
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,55420
Polymers41,8081
Non-polymers1,74619
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)98.701, 111.245, 160.084
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUAA89 - 41015 - 336
21GLUGLUBB89 - 41015 - 336
12THRTHRAA86 - 41012 - 336
22THRTHRCC86 - 41012 - 336
13GLNGLNAA88 - 41014 - 336
23GLNGLNDD88 - 41014 - 336
14GLUGLUBB89 - 41015 - 336
24GLUGLUCC89 - 41015 - 336
15GLUGLUBB89 - 41015 - 336
25GLUGLUDD89 - 41015 - 336
16GLNGLNCC88 - 41014 - 336
26GLNGLNDD88 - 41014 - 336

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
cAMP-specific 3',5'-cyclic phosphodiesterase 4D / DPDE3 / PDE43


Mass: 41808.242 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: residues 381-740 / Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Plasmid: pET15b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): codon plus
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 8 types, 833 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 50 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-J2E / 1-cycloheptyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazol-5-one


Mass: 398.538 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H34N2O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 762 / 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: 2.63 Å3/Da / Density % sol: 53.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 24% PEG 3350, 30% Ethylene glycol, 0.1 M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97622 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 12, 2016 / Details: CRL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97622 Å / Relative weight: 1
ReflectionResolution: 1.83→160.08 Å / Num. obs: 155099 / % possible obs: 100 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.025 / Rrim(I) all: 0.066 / Net I/σ(I): 17.6
Reflection shellResolution: 1.83→1.86 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.944 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 7689 / CC1/2: 0.699 / Rpim(I) all: 0.389 / Rrim(I) all: 1.022 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SL3

3sl3


Resolution: 1.83→84.16 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.955 / SU B: 2.631 / SU ML: 0.079 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.114 / ESU R Free: 0.11 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2082 7787 5 %RANDOM
Rwork0.1789 ---
obs0.1804 147210 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 124.96 Å2 / Biso mean: 36.868 Å2 / Biso min: 17.63 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å2-0 Å2-0 Å2
2---0.86 Å20 Å2
3---0.97 Å2
Refinement stepCycle: final / Resolution: 1.83→84.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10551 0 421 762 11734
Biso mean--63.44 45.37 -
Num. residues----1304
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01311154
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710375
X-RAY DIFFRACTIONr_angle_refined_deg1.5631.65415050
X-RAY DIFFRACTIONr_angle_other_deg1.4481.58324095
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4351304
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.15223.615603
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.071151922
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8621552
X-RAY DIFFRACTIONr_chiral_restr0.0890.21450
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212025
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022135
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A109900.08
12B109900.08
21A110500.09
22C110500.09
31A110590.08
32D110590.08
41B109840.08
42C109840.08
51B110930.08
52D110930.08
61C110670.07
62D110670.07
LS refinement shellResolution: 1.831→1.879 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 532 -
Rwork0.278 10786 -
all-11318 -
obs--99.88 %

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