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- PDB-5wh6: Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91) -

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Basic information

Entry
Database: PDB / ID: 5wh6
TitleCrystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91)
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHydrolase/Hydrolase Inhibitor / Phosphodiesterase / inhibitor Zl-n-91 / PDE4D-S91 complex / Hydrolase-Hydrolase Inhibitor complex
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-AKJ / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.6 Å
AuthorsKe, H. / Wang, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM59791 United States
CitationJournal: Biochemistry / Year: 2018
Title: Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors.
Authors: Feng, X. / Wang, H. / Ye, M. / Xu, X.T. / Xu, Y. / Yang, W. / Zhang, H.T. / Song, G. / Ke, H.
History
DepositionJul 14, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 18, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2019Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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.ptnr1_symmetry / _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_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,5519
Polymers115,7192
Non-polymers8327
Water6,918384
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,2885
Polymers57,8601
Non-polymers4284
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)58,2644
Polymers57,8601
Non-polymers4043
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.948, 80.197, 163.670
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cAMP-specific 3',5'-cyclic phosphodiesterase 4D / DPDE3 / PDE43


Mass: 57859.504 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical ChemComp-AKJ / 1-[4-(difluoromethoxy)-3-{[(3S)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one


Mass: 314.324 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H20F2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 384 / 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

Crystal growTemperature: 277 K / Method: evaporation / pH: 7.5
Details: The ~10mg/ml PDE4D2 (86-413) was stored in a buffer of 20 mM Tris.base, pH 7.5, 50 mM NaCl, 1 mM 2-mercaptoethanol, 1 mM EDTA and mixed with 2 mM (R)- or (S)-5. They were crystallized at 4C ...Details: The ~10mg/ml PDE4D2 (86-413) was stored in a buffer of 20 mM Tris.base, pH 7.5, 50 mM NaCl, 1 mM 2-mercaptoethanol, 1 mM EDTA and mixed with 2 mM (R)- or (S)-5. They were crystallized at 4C by hanging drop against a well buffer of 0.1 M HEPES pH 7.5, 15% PEG3350, 30% ethylene glycol, and 10% isopropanol.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1 Å
DetectorType: Bruker AXIOM 200 / Detector: CCD / Date: Apr 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→81 Å / Num. obs: 95949 / % possible obs: 93.1 % / Redundancy: 12.6 % / Rmerge(I) obs: 0.068 / Net I/σ(I): 10.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementResolution: 1.6→30 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.95 / SU B: 2.036 / SU ML: 0.069 / Cross valid method: THROUGHOUT / ESU R: 0.099 / ESU R Free: 0.094 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2243 4724 4.9 %RANDOM
Rwork0.20619 ---
obs0.20707 91110 92.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 28.358 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å2-0 Å2
2---0.03 Å20 Å2
3----0.02 Å2
Refinement stepCycle: 1 / Resolution: 1.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5271 0 49 384 5704
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0195437
X-RAY DIFFRACTIONr_bond_other_d0.0010.025156
X-RAY DIFFRACTIONr_angle_refined_deg0.9241.9527370
X-RAY DIFFRACTIONr_angle_other_deg0.734311853
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.2685649
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.38925.147272
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.02415957
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.3741526
X-RAY DIFFRACTIONr_chiral_restr0.050.2850
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026087
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021235
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_it0.9772.7272602
X-RAY DIFFRACTIONr_mcbond_other0.9762.7262601
X-RAY DIFFRACTIONr_mcangle_it1.6484.0833249
X-RAY DIFFRACTIONr_mcangle_other1.6484.0833250
X-RAY DIFFRACTIONr_scbond_it1.2112.8552835
X-RAY DIFFRACTIONr_scbond_other1.212.8552836
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.0214.2254122
X-RAY DIFFRACTIONr_long_range_B_refined3.9822.1656771
X-RAY DIFFRACTIONr_long_range_B_other3.75921.8876620
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.263 206 -
Rwork0.281 3933 -
obs--54.95 %

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