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- PDB-3g4l: Crystal structure of human phosphodiesterase 4d with roflumilast -

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Basic information

Entry
Database: PDB / ID: 3g4l
TitleCrystal structure of human phosphodiesterase 4d with roflumilast
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / phosphodiesterase / PDE4D / Alternative splicing / cAMP / Cytoplasm / Cytoskeleton / Membrane / Metal-binding / Phosphoprotein
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-ROF / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsStaker, B.L.
CitationJournal: Nat.Biotechnol. / Year: 2010
Title: Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
Authors: Burgin, A.B. / Magnusson, O.T. / Singh, J. / Witte, P. / Staker, B.L. / Bjornsson, J.M. / Thorsteinsdottir, M. / Hrafnsdottir, S. / Hagen, T. / Kiselyov, A.S. / Stewart, L.J. / Gurney, M.E.
History
DepositionFeb 3, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
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_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)178,01328
Polymers175,1614
Non-polymers2,85224
Water3,405189
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5658
Polymers43,7901
Non-polymers7757
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)44,5037
Polymers43,7901
Non-polymers7136
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)44,4416
Polymers43,7901
Non-polymers6515
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)44,5037
Polymers43,7901
Non-polymers7136
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.665, 111.952, 161.701
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
31C
41D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1115A260 - 578
2115B260 - 578
3115C260 - 578
4115D260 - 578
DetailsUNKNOWN

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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: residues 380-753 / Mutation: S715A, S717A
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-nucleotide phosphodiesterase

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Non-polymers , 6 types, 213 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.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-ROF / 3-(CYCLOPROPYLMETHOXY)-N-(3,5-DICHLOROPYRIDIN-4-YL)-4-(DIFLUOROMETHOXY)BENZAMIDE / ROFLUMILAST


Mass: 403.207 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H14Cl2F2N2O3
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / 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: 2.58 Å3/Da / Density % sol: 52.23 %
Crystal growTemperature: 293 K / pH: 7.5
Details: 100MM HEPES PH 7.5, 35% ETHYLENE GLYCOL, 5% GLYCEROL, 22% PEG 3350, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97
RadiationProtocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 63001 / % possible obs: 99.4 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 5.4
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 6 % / Rmerge(I) obs: 0.616 / % possible all: 97.3

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.2.0019refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→50 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.899 / SU B: 9.121 / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.452 / ESU R Free: 0.283 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE
RfactorNum. reflection% reflectionSelection details
Rfree0.259 3187 5.1 %RANDOM
Rwork0.214 ---
obs0.217 62929 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.63 Å2
Baniso -1Baniso -2Baniso -3
1--0.28 Å20 Å20 Å2
2---0.19 Å20 Å2
3---0.47 Å2
Refinement stepCycle: LAST / Resolution: 2.5→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10589 0 164 189 10942
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.02110960
X-RAY DIFFRACTIONr_bond_other_d0.0020.027117
X-RAY DIFFRACTIONr_angle_refined_deg1.2781.95814888
X-RAY DIFFRACTIONr_angle_other_deg1.009317458
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.24451308
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.75225.157543
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.051151906
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2371551
X-RAY DIFFRACTIONr_chiral_restr0.1580.21709
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212039
X-RAY DIFFRACTIONr_gen_planes_other0.0060.022084
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_refined0.1560.2382
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.4460.23
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2340.232
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2540.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4361.56569
X-RAY DIFFRACTIONr_mcbond_other0.1421.52615
X-RAY DIFFRACTIONr_mcangle_it0.845210691
X-RAY DIFFRACTIONr_scbond_it1.32434391
X-RAY DIFFRACTIONr_scangle_it2.1574.54185
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Auth asym-IDNumberTypeRms dev position (Å)Weight position
A1878medium positional0.170.5
B1878medium positional0.190.5
C1878medium positional0.190.5
D1878medium positional0.150.5
A2322loose positional0.45
B2322loose positional0.455
C2322loose positional0.445
D2322loose positional0.395
A1878medium thermal0.632
B1878medium thermal12
C1878medium thermal0.642
D1878medium thermal1.072
A2322loose thermal0.6410
B2322loose thermal0.8810
C2322loose thermal0.6110
D2322loose thermal0.9110
LS refinement shellResolution: 2.5→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 220 -
Rwork0.305 4225 -
obs--96.63 %

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