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

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Basic information

Entry
Database: PDB / ID: 6hwo
TitleCrystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-1335
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) / 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-FFZ / DI(HYDROXYETHYL)ETHER / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsSingh, A.K. / Brown, D.G.
Funding support1items
OrganizationGrant numberCountry
European Union602666
CitationJournal: Bioorg.Med.Chem. / Year: 2019
Title: Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2).
Authors: de Heuvel, E. / Singh, A.K. / Boronat, P. / Kooistra, A.J. / van der Meer, T. / Sadek, P. / Blaazer, A.R. / Shaner, N.C. / Bindels, D.S. / Caljon, G. / Maes, L. / Sterk, G.J. / Siderius, M. ...Authors: de Heuvel, E. / Singh, A.K. / Boronat, P. / Kooistra, A.J. / van der Meer, T. / Sadek, P. / Blaazer, A.R. / Shaner, N.C. / Bindels, D.S. / Caljon, G. / Maes, L. / Sterk, G.J. / Siderius, M. / Oberholzer, M. / de Esch, I.J.P. / Brown, D.G. / Leurs, R.
History
DepositionOct 12, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2019Group: Data collection / Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 4, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 24, 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_initial_refinement_model / 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
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)174,29879
Polymers167,2334
Non-polymers7,06575
Water10,629590
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,73522
Polymers41,8081
Non-polymers1,92721
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)43,39717
Polymers41,8081
Non-polymers1,58916
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)43,25715
Polymers41,8081
Non-polymers1,44814
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)43,90925
Polymers41,8081
Non-polymers2,10124
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)98.465, 110.848, 160.461
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, 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, 665 molecules

#2: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 51 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-FFZ / 3-[5-[(4aR,8aS)-4-OXIDANYLIDENE-3-PROPAN-2-YL-4a,5,8,8a-TETRAHYDROPHTHALAZIN-1-YL]-2-METHOXY-PHENYL]-N-(PHENYLMETHYL)PROP-2-YNAMIDE


Mass: 455.548 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H29N3O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#7: Chemical
ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#8: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 590 / 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: 2.62 Å3/Da / Density % sol: 53.1 %
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: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 16, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.99→80.19 Å / Num. obs: 120894 / % possible obs: 100 % / Redundancy: 6.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.028 / Rrim(I) all: 0.071 / Net I/σ(I): 14.1
Reflection shellResolution: 1.99→2.04 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.79 / Mean I/σ(I) obs: 2 / Num. unique obs: 8845 / CC1/2: 0.589 / Rpim(I) all: 0.333 / Rrim(I) all: 0.859 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
DIALSdata reduction
Aimlessdata scaling
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SL3

3sl3


Resolution: 1.99→80.19 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.932 / SU B: 5.079 / SU ML: 0.134 / Cross valid method: THROUGHOUT / ESU R: 0.169 / ESU R Free: 0.167 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25539 5954 5 %RANDOM
Rwork0.19819 ---
obs0.20108 112544 97.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 43.247 Å2
Baniso -1Baniso -2Baniso -3
1-0.76 Å20 Å2-0 Å2
2---1.23 Å20 Å2
3---0.48 Å2
Refinement stepCycle: 1 / Resolution: 1.99→80.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10485 0 455 590 11530
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.01911151
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210321
X-RAY DIFFRACTIONr_angle_refined_deg1.9351.95715015
X-RAY DIFFRACTIONr_angle_other_deg1.1152.98423945
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.26951299
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.69424.792553
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.23151913
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0941552
X-RAY DIFFRACTIONr_chiral_restr0.1320.21707
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212003
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022109
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_it3.8964.1145199
X-RAY DIFFRACTIONr_mcbond_other3.8964.1145198
X-RAY DIFFRACTIONr_mcangle_it5.2066.1516497
X-RAY DIFFRACTIONr_mcangle_other5.2066.1526498
X-RAY DIFFRACTIONr_scbond_it4.714.5955952
X-RAY DIFFRACTIONr_scbond_other4.7094.5955952
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.6056.6848519
X-RAY DIFFRACTIONr_long_range_B_refined8.93650.35513298
X-RAY DIFFRACTIONr_long_range_B_other8.93550.35713299
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.989→2.04 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.407 361 -
Rwork0.364 7924 -
obs--93.57 %

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