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

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Basic information

Entry
Database: PDB / ID: 7aag
TitleCrystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-617
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 heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of interleukin-5 production / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / heterocyclic compound binding / beta-2 adrenergic receptor binding ...signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of interleukin-5 production / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / heterocyclic compound binding / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / adrenergic receptor signaling pathway / cAMP catabolic process / regulation of cell communication by electrical coupling involved in cardiac conduction / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / DARPP-32 events / : / positive regulation of heart rate / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to epinephrine stimulus / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / cellular response to cAMP / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / calcium channel regulator activity / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / nuclear membrane / G alpha (s) signalling events / transmembrane transporter binding / cilium / apical plasma membrane / centrosome / enzyme binding / nucleoplasm / metal ion binding / membrane / 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
ISOLEUCINE / DI(HYDROXYETHYL)ETHER / PROLINE / Chem-QWT / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 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-617
Authors: Singh, A.K. / Brown, D.G.
History
DepositionSep 4, 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)175,81291
Polymers167,2334
Non-polymers8,57987
Water15,817878
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,13527
Polymers41,8081
Non-polymers2,32726
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)43,77619
Polymers41,8081
Non-polymers1,96818
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)43,81220
Polymers41,8081
Non-polymers2,00419
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)44,08925
Polymers41,8081
Non-polymers2,28024
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)98.440, 110.820, 161.030
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: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUILEILEAA89 - 41015 - 336
21GLUGLUILEILEBB89 - 41015 - 336
12GLNGLNSERSERAA88 - 40814 - 334
22GLNGLNSERSERCC88 - 40814 - 334
13GLNGLNILEILEAA88 - 41014 - 336
23GLNGLNILEILEDD88 - 41014 - 336
14GLUGLUSERSERBB89 - 40815 - 334
24GLUGLUSERSERCC89 - 40815 - 334
15GLUGLUILEILEBB89 - 41015 - 336
25GLUGLUILEILEDD89 - 41015 - 336
16GLNGLNSERSERCC88 - 40814 - 334
26GLNGLNSERSERDD88 - 40814 - 334

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 , 10 types, 965 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.: 5 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-QWT / 1-cycloheptyl-3-(4-methoxy-3-{4-[4-(1H-1,2,3,4-tetrazol-5-yl)phenoxy]butoxy}phenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazol-5-one / 2-cycloheptyl-5-[4-methoxy-3-[4-[4-(1~{H}-1,2,3,4-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4,4-dimethyl-pyrazol-3-one


Mass: 546.661 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H38N6O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 50 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical
ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#9: Chemical ChemComp-ILE / ISOLEUCINE


Type: L-peptide linking / Mass: 131.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO2
#10: Chemical ChemComp-PRO / PROLINE


Type: L-peptide linking / Mass: 115.130 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H9NO2
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 878 / 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: 53.25 %
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: I04 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.79→66.94 Å / Num. obs: 165809 / % possible obs: 100 % / Redundancy: 6.7 % / CC1/2: 0.99 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.052 / Rrim(I) all: 0.099 / Net I/σ(I): 13.5
Reflection shellResolution: 1.79→1.84 Å / Redundancy: 6.8 % / Rmerge(I) obs: 1.26 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 12112 / CC1/2: 0.52 / Rpim(I) all: 0.789 / Rrim(I) all: 1.495 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SL3

3sl3


Resolution: 1.79→66.94 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.958 / SU B: 2.5 / SU ML: 0.074 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.101 / ESU R Free: 0.099 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1967 8357 5 %RANDOM
Rwork0.1667 ---
obs0.1682 157351 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 115.66 Å2 / Biso mean: 30.396 Å2 / Biso min: 8.53 Å2
Baniso -1Baniso -2Baniso -3
1-0.37 Å2-0 Å2-0 Å2
2---1.03 Å20 Å2
3---0.66 Å2
Refinement stepCycle: final / Resolution: 1.79→66.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10520 0 542 878 11940
Biso mean--52.92 41.48 -
Num. residues----1300
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01311264
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710480
X-RAY DIFFRACTIONr_angle_refined_deg1.6381.65215181
X-RAY DIFFRACTIONr_angle_other_deg1.4681.60424318
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.70651309
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.46523.829598
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.264151924
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0461552
X-RAY DIFFRACTIONr_chiral_restr0.0930.21459
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212573
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022160
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A109560.09
12B109560.09
21A109320.09
22C109320.09
31A111050.08
32D111050.08
41B109450.09
42C109450.09
51B111650.08
52D111650.08
61C110810.07
62D110810.07
LS refinement shellResolution: 1.79→1.836 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 641 -
Rwork0.298 11455 -
all-12096 -
obs--100 %

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