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Basic information

Entry
Database: PDB / ID: 5lbo
TitleCrystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-001
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 / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / heterocyclic compound binding / positive regulation of heart rate / adrenergic receptor signaling pathway / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-serine phosphorylation / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / DARPP-32 events / 3',5'-cyclic-GMP phosphodiesterase activity / calcium channel regulator activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to cAMP / cAMP-mediated signaling / calcium channel complex / cellular response to epinephrine stimulus / positive regulation of interleukin-2 production / regulation of heart rate / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / G alpha (s) signalling events / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / membrane / nucleus / metal ion binding / 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-6M5 / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / DI(HYDROXYETHYL)ETHER / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsSingh, A.K. / Brown, D.G.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.
Authors: Blaazer, A.R. / Singh, A.K. / de Heuvel, E. / Edink, E. / Orrling, K.M. / Veerman, J.J.N. / van den Bergh, T. / Jansen, C. / Balasubramaniam, E. / Mooij, W.J. / Custers, H. / Sijm, M. / ...Authors: Blaazer, A.R. / Singh, A.K. / de Heuvel, E. / Edink, E. / Orrling, K.M. / Veerman, J.J.N. / van den Bergh, T. / Jansen, C. / Balasubramaniam, E. / Mooij, W.J. / Custers, H. / Sijm, M. / Tagoe, D.N.A. / Kalejaiye, T.D. / Munday, J.C. / Tenor, H. / Matheeussen, A. / Wijtmans, M. / Siderius, M. / de Graaf, C. / Maes, L. / de Koning, H.P. / Bailey, D.S. / Sterk, G.J. / de Esch, I.J.P. / Brown, D.G. / Leurs, R.
History
DepositionJun 16, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 14, 2018Provider: repository / Type: Initial release
Revision 1.1May 2, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 23, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Jan 10, 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 / 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)172,82051
Polymers167,2334
Non-polymers5,58747
Water9,962553
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,28814
Polymers41,8081
Non-polymers1,47913
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)43,15512
Polymers41,8081
Non-polymers1,34711
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)42,9699
Polymers41,8081
Non-polymers1,1618
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)43,40816
Polymers41,8081
Non-polymers1,60015
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)98.223, 111.092, 160.798
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: _ / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUAA89 - 41015 - 336
21GLUGLUBB89 - 41015 - 336
12GLUGLUAA89 - 41015 - 336
22GLUGLUCC89 - 41015 - 336
13GLNGLNAA88 - 41014 - 336
23GLNGLNDD88 - 41014 - 336
14GLUGLUBB89 - 41015 - 336
24GLUGLUCC89 - 41015 - 336
15GLUGLUBB89 - 41015 - 336
25GLUGLUDD89 - 41015 - 336
16GLUGLUCC89 - 41015 - 336
26GLUGLUDD89 - 41015 - 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: UNP 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, 600 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.: 28 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL


Mass: 154.251 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O2S2
#6: Chemical
ChemComp-6M5 / (4~{a}~{S},8~{a}~{R})-2-cycloheptyl-4-[4-methoxy-3-[4-[4-(1~{H}-1,2,3,4-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4~{a},5,8,8~{a}-tetrahydrophthalazin-1-one


Mass: 584.708 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H40N6O4
#7: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#8: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


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


Mass: 18.015 Da / Num. of mol.: 553 / 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: 53.19 %
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: 0.97623 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 28, 2016 / Details: CRL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97623 Å / Relative weight: 1
ReflectionResolution: 2.25→160.8 Å / Num. obs: 80611 / % possible obs: 96.4 % / Redundancy: 6.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.113 / Net I/σ(I): 13.8
Reflection shellResolution: 2.25→2.38 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.763 / Mean I/σ(I) obs: 2.6 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SL3

3sl3


Resolution: 2.25→91.4 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.942 / SU B: 5.815 / SU ML: 0.137 / Cross valid method: THROUGHOUT / ESU R: 0.247 / ESU R Free: 0.189
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U values refined individually
RfactorNum. reflection% reflectionSelection details
Rfree0.20965 4023 5 %RANDOM
Rwork0.17365 ---
obs0.1754 76504 96.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.341 Å2
Baniso -1Baniso -2Baniso -3
1-1.17 Å20 Å20 Å2
2---2.19 Å20 Å2
3---1.02 Å2
Refinement stepCycle: 1 / Resolution: 2.25→91.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10526 0 360 553 11439
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.01911128
X-RAY DIFFRACTIONr_bond_other_d0.010.0210634
X-RAY DIFFRACTIONr_angle_refined_deg1.6991.9515049
X-RAY DIFFRACTIONr_angle_other_deg1.6492.97724453
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1851305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.56325.074544
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.572151915
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.261552
X-RAY DIFFRACTIONr_chiral_restr0.1040.21710
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212330
X-RAY DIFFRACTIONr_gen_planes_other0.0080.022516
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_it3.7954.1765220
X-RAY DIFFRACTIONr_mcbond_other3.7954.1765219
X-RAY DIFFRACTIONr_mcangle_it5.3256.2486525
X-RAY DIFFRACTIONr_mcangle_other5.3256.2486526
X-RAY DIFFRACTIONr_scbond_it5.1854.7465908
X-RAY DIFFRACTIONr_scbond_other5.1844.7465909
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.7536.8748525
X-RAY DIFFRACTIONr_long_range_B_refined9.56433.74413325
X-RAY DIFFRACTIONr_long_range_B_other9.56433.74613326
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)
11A412440.08
12B412440.08
21A414560.07
22C414560.07
31A418500.07
32D418500.07
41B416120.07
42C416120.07
51B417400.07
52D417400.07
61C416440.07
62D416440.07
LS refinement shellResolution: 2.255→2.313 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 293 -
Rwork0.275 5803 -
obs--99.97 %

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