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- PDB-5laq: Crystal structure of human phosphodiesterase 4B catalytic domain ... -

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Basic information

Entry
Database: PDB / ID: 5laq
TitleCrystal structure of human phosphodiesterase 4B catalytic domain with inhibitor NPD-001
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4B,cAMP-specific 3',5'-cyclic phosphodiesterase 4B
KeywordsHYDROLASE / Phosphodiesterase / cAMP / alternative splicing
Function / homology
Function and homology information


negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / gamma-tubulin complex / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / neutrophil homeostasis / gamma-tubulin binding / regulation of cardiac muscle cell contraction / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / leukocyte migration ...negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / gamma-tubulin complex / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / neutrophil homeostasis / gamma-tubulin binding / regulation of cardiac muscle cell contraction / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / leukocyte migration / cAMP catabolic process / excitatory synapse / DARPP-32 events / 3',5'-cyclic-GMP phosphodiesterase activity / calcium channel regulator activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / cAMP-mediated signaling / cellular response to epinephrine stimulus / neutrophil chemotaxis / positive regulation of interleukin-2 production / Z disc / positive regulation of type II interferon production / cellular response to xenobiotic stimulus / synaptic vesicle / T cell receptor signaling pathway / cellular response to lipopolysaccharide / transmembrane transporter binding / dendritic spine / postsynaptic density / centrosome / perinuclear region of cytoplasm / nucleus / metal ion binding / 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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-6M5 / ACETATE ION / 3',5'-cyclic-AMP phosphodiesterase 4B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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 14, 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 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.4Jan 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
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_label_atom_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 4B,cAMP-specific 3',5'-cyclic phosphodiesterase 4B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,2947
Polymers48,4431
Non-polymers8526
Water1,53185
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area860 Å2
ΔGint-51 kcal/mol
Surface area15040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.737, 95.737, 85.113
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein cAMP-specific 3',5'-cyclic phosphodiesterase 4B,cAMP-specific 3',5'-cyclic phosphodiesterase 4B / DPDE4 / PDE32


Mass: 48442.699 Da / Num. of mol.: 1
Fragment: UNP residues 241-659, Catalytic domain UNP residues 305-659
Source method: isolated from a genetically manipulated source
Details: linker is from PDE4C that was swapped to replace the natural linker
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4B, DPDE4 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q07343, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 91 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#5: 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.: 1 / Source method: obtained synthetically / Formula: C33H40N6O4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 85 / 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: 2.35 Å3/Da / Density % sol: 47.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 50 mM calcium acetate, 20% PEG 400, 100 mM sodium acetate

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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: 2.4→82.91 Å / Num. obs: 17941 / % possible obs: 100 % / Redundancy: 8.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.129 / Net I/σ(I): 13
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.78 / Mean I/σ(I) obs: 2.3 / % 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: 3G45

3g45


Resolution: 2.4→82.91 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.931 / SU B: 8.475 / SU ML: 0.193 / Cross valid method: THROUGHOUT / ESU R: 0.295 / ESU R Free: 0.24
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U values refined individually
RfactorNum. reflection% reflectionSelection details
Rfree0.24084 744 4.2 %RANDOM
Rwork0.17113 ---
obs0.17408 17166 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 51.062 Å2
Baniso -1Baniso -2Baniso -3
1-1.03 Å20.51 Å20 Å2
2--1.03 Å20 Å2
3----3.33 Å2
Refinement stepCycle: 1 / Resolution: 2.4→82.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2720 0 57 85 2862
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0192833
X-RAY DIFFRACTIONr_bond_other_d0.0020.022652
X-RAY DIFFRACTIONr_angle_refined_deg1.5821.9393838
X-RAY DIFFRACTIONr_angle_other_deg12.9776099
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9145336
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.61125140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.50915493
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.4171513
X-RAY DIFFRACTIONr_chiral_restr0.0880.2431
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023189
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02655
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_it3.5894.8161350
X-RAY DIFFRACTIONr_mcbond_other3.5664.8081346
X-RAY DIFFRACTIONr_mcangle_it5.2437.2021682
X-RAY DIFFRACTIONr_mcangle_other5.2437.2071683
X-RAY DIFFRACTIONr_scbond_it4.5525.3251483
X-RAY DIFFRACTIONr_scbond_other4.5515.3271484
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.0657.7642157
X-RAY DIFFRACTIONr_long_range_B_refined8.67938.4053422
X-RAY DIFFRACTIONr_long_range_B_other8.67838.4063423
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.404→2.467 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 46 -
Rwork0.244 1257 -
obs--99.85 %

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