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- PDB-6fe7: Crystal structure of human phosphodiesterase 4D2 catalytic domain... -

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Basic information

Entry
Database: PDB / ID: 6fe7
TitleCrystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-356
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) / 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-D62 / DI(HYDROXYETHYL)ETHER / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsSingh, A.K. / Brown, D.G.
CitationJournal: To be published
Title: hPDE4D2 structure with inhibitor NPD-356
Authors: Salado, I.G. / Moreno, C. / Sakaine, G. / Singh, A.K. / Blaazer, A.R. / Siderius, M. / Matheeussen, A. / Gul, S. / Maes, L. / Leurs, R. / Brown, D.G. / Augustyns, K.
History
DepositionDec 29, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 10, 2019Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim
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 / _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)176,33295
Polymers167,2334
Non-polymers9,09991
Water12,070670
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,22326
Polymers41,8081
Non-polymers2,41425
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)43,93022
Polymers41,8081
Non-polymers2,12221
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)44,12523
Polymers41,8081
Non-polymers2,31622
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)44,05424
Polymers41,8081
Non-polymers2,24623
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)98.220, 111.030, 160.960
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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
12GLNGLNILEILEAA88 - 41014 - 336
22GLNGLNILEILECC88 - 41014 - 336
13GLNGLNILEILEAA88 - 41014 - 336
23GLNGLNILEILEDD88 - 41014 - 336
14GLUGLUILEILEBB89 - 41015 - 336
24GLUGLUILEILECC89 - 41015 - 336
15GLUGLUILEILEBB89 - 41015 - 336
25GLUGLUILEILEDD89 - 41015 - 336
16GLNGLNPROPROCC88 - 41114 - 337
26GLNGLNPROPRODD88 - 41114 - 337

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, 761 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


Mass: 62.068 Da / Num. of mol.: 58 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-D62 / (4aS,8aR)-2-(1-{2-aminothieno[2,3-d]pyrimidin-4-yl}piperidin-4-yl)-4-(3,4- dimethoxyphenyl)-1,2,4a,5,8,8a-hexahydrophthalazin-1-one


Mass: 518.631 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H30N6O3S
#7: 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
#8: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 670 / 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: 2.63 Å3/Da / Density % sol: 53.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 24% PEG 3350, 30% Ethylene Glycol, 0.1 M HEPES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97624 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 8, 2017 / Details: CRL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97624 Å / Relative weight: 1
ReflectionResolution: 2→54.3 Å / Num. obs: 119295 / % possible obs: 100 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.042 / Rrim(I) all: 0.108 / Net I/σ(I): 12.3
Reflection shellResolution: 2→2.05 Å / Redundancy: 6.8 % / Rmerge(I) obs: 1.3 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 8760 / CC1/2: 0.547 / Rpim(I) all: 0.538 / Rrim(I) all: 1.408 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
XDSdata reduction
Aimless0.5.31data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→54.3 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.957 / SU B: 3.869 / SU ML: 0.101 / Cross valid method: THROUGHOUT / ESU R: 0.146 / ESU R Free: 0.131
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U values refined individually
RfactorNum. reflection% reflectionSelection details
Rfree0.20001 6067 5.1 %RANDOM
Rwork0.16963 ---
obs0.17118 113139 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 40.372 Å2
Baniso -1Baniso -2Baniso -3
1-0.98 Å20 Å20 Å2
2---1.11 Å20 Å2
3---0.13 Å2
Refinement stepCycle: 1 / Resolution: 2→54.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10526 0 587 670 11783
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.01911284
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210495
X-RAY DIFFRACTIONr_angle_refined_deg1.8941.96215168
X-RAY DIFFRACTIONr_angle_other_deg1.0962.98424371
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.14251301
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.0524.991545
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.324151915
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5331552
X-RAY DIFFRACTIONr_chiral_restr0.1120.21711
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212046
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022098
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.4933.7495210
X-RAY DIFFRACTIONr_mcbond_other3.4923.7495209
X-RAY DIFFRACTIONr_mcangle_it4.4075.6036509
X-RAY DIFFRACTIONr_mcangle_other4.4065.6046510
X-RAY DIFFRACTIONr_scbond_it5.1764.2996074
X-RAY DIFFRACTIONr_scbond_other5.1764.2996074
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.1156.2198660
X-RAY DIFFRACTIONr_long_range_B_refined8.30246.58513406
X-RAY DIFFRACTIONr_long_range_B_other8.30346.5913407
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A221820.08
12B221820.08
21A222520.08
22C222520.08
31A224500.07
32D224500.07
41B222560.08
42C222560.08
51B225240.07
52D225240.07
61C222640.08
62D222640.08
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.288 415 -
Rwork0.281 8333 -
obs--99.99 %

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