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- PDB-5tkb: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 4D IN COMPLEX WITH A... -

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Basic information

Entry
Database: PDB / ID: 5tkb
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 4D IN COMPLEX WITH A TETRAFLUORANLINE COMPOUND
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE/HYDROLASE inhibitor / PHOSPHODIESTERASE / PDE4D / ALTERNATIVE SPLICING / CAMP / CYTOPLASM / CYTOSKELETON / HYDROLASE / MEMBRANE / METAL- BINDING / PHOSPHOPROTEIN / HYDROLASE-HYDROLASE inhibitor complex
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 / 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 relaxation of cardiac muscle / negative regulation of heart contraction / 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 / calcium channel complex / cellular response to epinephrine stimulus / 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-7DJ / ETHANOL / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsSack, J.S.
CitationJournal: Medchemcomm / Year: 2017
Title: Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling.
Authors: Moslin, R. / Gardner, D. / Santella, J. / Zhang, Y. / Duncia, J.V. / Liu, C. / Lin, J. / Tokarski, J.S. / Strnad, J. / Pedicord, D. / Chen, J. / Blat, Y. / Zupa-Fernandez, A. / Cheng, L. / ...Authors: Moslin, R. / Gardner, D. / Santella, J. / Zhang, Y. / Duncia, J.V. / Liu, C. / Lin, J. / Tokarski, J.S. / Strnad, J. / Pedicord, D. / Chen, J. / Blat, Y. / Zupa-Fernandez, A. / Cheng, L. / Sun, H. / Chaudhry, C. / Huang, C. / D'Arienzo, C. / Sack, J.S. / Muckelbauer, J.K. / Chang, C. / Tredup, J. / Xie, D. / Aranibar, N. / Burke, J.R. / Carter, P.H. / Weinstein, D.S.
History
DepositionOct 6, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 4, 2023Group: 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

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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)177,94627
Polymers175,1614
Non-polymers2,78523
Water8,485471
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5578
Polymers43,7901
Non-polymers7667
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5578
Polymers43,7901
Non-polymers7667
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4646
Polymers43,7901
Non-polymers6745
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3685
Polymers43,7901
Non-polymers5784
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.000, 112.700, 159.880
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: 43790.168 Da / Num. of mol.: 4 / Fragment: UNP RESIDUES 380-753 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Plasmid: PBACGUS / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 6 types, 494 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-EOH / ETHANOL


Mass: 46.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O
#6: Chemical
ChemComp-7DJ / N-[(2R)-2,3-dihydroxy-2-methylpropyl]-8-(methylamino)-6-[(2,3,5,6-tetrafluorophenyl)amino]imidazo[1,2-b]pyridazine-3-carboxamide


Mass: 442.368 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H18F4N6O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 471 / 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: 2.55 Å3/Da / Density % sol: 51.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100mM HEPES, pH 7.5, 35% Ethylene Glycol, 5% Glycerol, 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 14, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.16→112.71 Å / Num. obs: 96469 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 6.7 % / Biso Wilson estimate: 38.87 Å2 / Rmerge(I) obs: 0.104 / Net I/σ(I): 12.2
Reflection shellResolution: 2.16→2.28 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.759 / Mean I/σ(I) obs: 2.3 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3G4I

3g4i


Resolution: 2.16→31.62 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.931 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.187 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.187 / SU Rfree Blow DPI: 0.152 / SU Rfree Cruickshank DPI: 0.153
RfactorNum. reflection% reflectionSelection details
Rfree0.209 4770 4.95 %RANDOM
Rwork0.188 ---
obs0.189 96348 100 %-
Displacement parametersBiso mean: 40.63 Å2
Baniso -1Baniso -2Baniso -3
1--4.8932 Å20 Å20 Å2
2--4.2347 Å20 Å2
3---0.6585 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 2.16→31.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10441 0 171 471 11083
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110812HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9714705HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3769SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes328HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1612HARMONIC5
X-RAY DIFFRACTIONt_it10812HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion17.36
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1428SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13129SEMIHARMONIC4
LS refinement shellResolution: 2.16→2.22 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.231 363 5.16 %
Rwork0.202 6671 -
all0.203 7034 -
obs--99.89 %

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